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 Textbook of
Craniofacial Growth
 Textbook of
Craniofacial Growth

Sridhar Premkumar BDS MDS

Reader
Department of Orthodontics
Tamil Nadu Government Dental College and Hospital
Chennai, Tamil Nadu, India

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

New Delhi • St Louis • Panama City • London
Published by
Jitendar P Vij
Jaypee Brothers Medical Publishers (P) Ltd

Corporate Office
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Textbook of Craniofacial Growth

© 2011, Jaypee Brothers Medical Publishers
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any
form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission
of the author and the publisher.
This book has been published in good faith that the material provided by author is original. Every effort is made to
ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent
error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only.
First Edition: 2011
ISBN 978-93-5025-182-9
Typeset at JPBMP typesetting unit
Printed at
 Dedicated to
the memory of
my parents
Shri KP Sridhar and
Mrs Sreemathy Sridhar
and
to all my teachers
who have played a role in
my growth and development
 Contributors

Dr Asish MDS
Orthodontist

Dr Poornima Raghuraman MDS

Lecturer, Department of Orthodontics
SRM Dental College, Ramapuram, Chennai, India

Dr Sumitha Muthukumar MDS

Orthodontist

Dr Badrinath Srinivasan MDS

Lecturer, Department of Orthodontics
Sri Ramachandra Dental College, Porur, Chennai, India

Dr Lavanya Hariharan MDS

Lecturer, Department of Oral and Maxillofacial Pathology
Ragas Dental College, Uthandi, Chennai, India

Dr Mona Mouneswari BDS

 Foreword

Science has developed phenomenally and likewise the field of orthodontics has also witnessed a phenomenal
amount of development. It is believed that writing a textbook is an obligation of the expert academician towards
students as well as to his colleagues in pursuit of continuing their education. An understanding of craniofacial
growth is essential for all dental surgeons and specialists like orthodontists, pedodontists and maxillofacial surgeons.
This textbook on craniofacial growth has been divided into 21 chapters, starting from development of bone
and cartilage till the etiology of developmental and acquired deformities. It has been written in a lucid, fluent
style which can be appreciated and understood by the average student as well as practitioner.
The importance of this book lies in the simplicity of its presentation which helps everyone understand the
concept and principles of craniofacial growth. Every BDS undergraduate should understand the concept of
orthodontics right from the basic level so that he or she can practice confidently as an individual. The design
and presentation of this book shows the meticulous and tireless effort of the author. The book covers the craniofacial
growth and its impact on orthodontics in detail. I am sure that this book will be of great help to dental students
and also to academically oriented dental surgeons.
I wish the author, for all success in his future endeavors.

Dr KSGA Nasser, MDS, AIMPT

Principal
Tamil Nadu Government Dental College and Hospital
Chennai, Tamil Nadu, India
 Preface

There is growing emphasis on the quality of treatment results, particularly from the aspects of prevention, interception
and correction of malocclusion. In spite of the level of knowledge acquired in their preclinical years, students
are unable to recall and relate facts and problems related to their training. This problem is more specific in relation
to the subject of craniofacial growth and development.
Craniofacial growth is a wonderful and fascinating phenomenon and understanding the fundamental aspects
of dentofacial growth and development is vital for every clinician to effectively deal with the complex problem
of abnormal skeletal growth of the jaws and dentoalveolar malocclusion. It is the author’s intent that this book
will be of value to those studying their undergraduate course in dentistry and more specifically, those who undergo
specialization training in the fields of orthodontics, pedodontics and oral and maxillofacial surgery.
The writing of a book is beset with many responsibilities. These are serious when the first edition is written.
The tide of many new thoughts ebb and flow through the years. The author must keep in mind the decision
of including the subject matter relevant to the intended purpose. The justification of presenting another textbook
on craniofacial growth to the shelves of dental literature is to be found in the presentation of subject matter
and novelty of its presentation. Adequate care is taken to ensure that this textbook on craniofacial growth is complete
in most of the aspects. Even development of emotional growth is included as a separate chapter. I sincerely
hope that the book will be of immense use for both the faculty and students, as the book is conceived both
as a teaching and a reference guide. It is hoped that this book together with future orthodontic research will
provide the bridge to a new era in the holistic treatment of the orthodontic patients.
Please mail your feedback to [email protected]

Sridhar Premkumar
 Acknowledgments

The author is conscious of the help rendered both directly and indirectly by his teachers, colleagues, students,
friends and well wishers. The following people need special acknowledgments for their help in bringing out this
book.
Dr KSGA Nasser, Principal, Tamil Nadu Government Dental College and Hospital, Chennai, Tamil Nadu, for
his constant encouragement, motivation and guidance right from the author’s college days.
Dr S Rangcharri, former Professor and Head, Department of Orthodontics, Tamil Nadu Government Dental
College and Hospital, Chennai, Tamil Nadu, the author’s postgraduate teacher who enlightened him with the
torch of knowledge in the field of orthodontics.
Dr MR Balasubramanian, the author’s teacher and currently, Dean, SRM Dental College, Chennai, Tamil
Nadu, for his constant guidance and enduring support during strategic points in his life.
Dr Mona Mouneswari, who helped with most of the illustrations and meticulous proofreading.
Dr Ramya Julian, Dr Catharin Maney, Dr Sathish Kumar and Dr Srirengalakshmi deserve special thanks for
their selfless and constant help in bringing out this book. Though many students have helped in different ways,
a note of gratitude to Saurab Jain, Sushma R, Prateshta Rajeevi Arvind and Sumaiya Parveen.
No book can be better than its publisher. The author would like to thank the publisher Shri Jitendar P Vij
of Jaypee Brothers Medical Publishers (P) Ltd, and also Mr Jayanandan and Mr KK Raman for their effective
coordination.
Closer to his home, the author would like to acknowledge his son Sriram and daughter Srinidhi, his energy
boosters, for their innocent love and affection. Finally, most fortunate authors have tolerant wives behind them.
The author’s wife has been one, having lost him for innumerable hours to the computer!
 Contents

1. Biology of Bone and Cartilage ................ 1 5. Control Mechanisms in

Classification of Bone ....................................... 1 Craniofacial Growth .............................. 57
Functions of Bone ............................................ 2 Changing Paradigms of
Gross Structure of Long Bone ........................ 2 Craniofacial Biology ....................................... 57
Types of Bone Tissue ....................................... 2 Site vs Center ................................................ 60
Molecular Structure of Bone ........................... 4 Controlling Factors in Craniofacial Growth ... 60
Skeletogenesis/Bone Formation ...................... 10 Theories of Bone Growth .............................. 63
Mechanism of Bone Growth ......................... 15
6. Postnatal Growth of the Craniofacial
Cartilage ......................................................... 17
Skeleton ................................................ 86
Postnatal Growth of Cranial Vault/Calvaria ... 86
2. Physiology of Bone ................................ 25
Cranial Base ................................................... 89
Bone Turnover ............................................... 25
Nasomaxillary Complex ................................. 92
Modeling and Remodeling ............................. 25
Mandible ........................................................ 97
Basic Multicellular Unit (BMU) ....................... 26
Temporomandibular Joint ............................ 104
Mechanical Influence on Bone ...................... 26
Dynamics of Facial Growth .......................... 105
Bone Regulators ............................................. 27
Purpose of Bone Remodeling ........................ 28 7. Development of Human Dentition,
Goals of Remodeling ..................................... 29 Supporting Structures
Remodeling Process ....................................... 29 and Occlusion ..................................... 109
Prenatal Development of Maxilla
3. Prenatal Craniofacial Growth ................ 33 and Mandible ............................................... 109
Period of Ovum ............................................. 33 Chronology of Human Dentition ................ 116
Period of Embryo .......................................... 34 Eruption of Tooth ........................................ 117
Fetal Period .................................................... 44 Evolution of Teeth ....................................... 123
Development of Temporomandibular Development of Occlusion ........................... 126
Joint (TMJ)..................................................... 44
Changing Relationships in Fetal Face ............ 44 8. Growth of Soft Tissues ........................ 137
Significance of Studying
4. Principles of Growth ............................. 46 Soft Tissue Growth ...................................... 137
Growth Pattern ............................................... 47 Methods of Studying Soft Tissue Growth
Mechanism of Bone Growth ......................... 50 and Assessment of Balanced Profile ............ 138
Growth Movements ....................................... 52 Soft Tissue Changes Due to Growth ........... 139
Growth Equivalents Concept/Enlow Soft Tissue Changes with
Counterpart Principle ..................................... 55 Treatment Procedures .................................. 144
 xvi Textbook of Craniofacial Growth

9. Adolescence and Craniofacial Schudy’s Concept ........................................ 224

Growth ................................................. 147 Dibbets’ Concept ......................................... 226
Endocrinology of Adolescence ..................... 147 Proffit’s Description of Rotation ................... 227
Timing of Puberty ........................................ 150 Growth Rotation of Maxilla ......................... 228
Pubertal Growth Spurt ................................ 150 Jaw Rotation and Tooth Eruption ............... 230
Clinical Features or Physical Changes of Mutual Relationship of
Pubertal Development ................................. 150 Rotating Jaw Bases ...................................... 230
Facial Growth During Puberty ..................... 151 Studies on Growth Rotations ....................... 232
Cephalometric Diagnosis in
10. Growth Studies and Assessment Growth Rotation .......................................... 234
of Age .................................................. 155
Methods of Growth Measurements ............. 155 14. Growth Patterns in
Craniometry ................................................. 156 Skeletal Malocclusion ......................... 236
Vital Staining ................................................ 156 Growth Pattern in Vertical
Histological Method ...................................... 157 Skeletal Disproportions ................................. 236
Histochemical Studies ................................... 157 Growth Pattern of Skeletal
Indirect Measurements ................................. 158 Class II Malocclusion .................................... 241
Serial Cephalometric Radiography Growth Pattern of
and Implantation .......................................... 159 Class III Malocclusions .................................. 245
Assessment of Age ....................................... 159 Sexual Dimorphism in
Skeletal Age Assessment ............................... 162 Various Malocclusions ................................... 247
Position of Glenoid Fossa
11. Craniometry, Anthropometry and in Different Facial Types ............................... 248
Cephalometrics in Growth .................. 175
Anthropometry ............................................. 175 15. Growth and Craniofacial Anomalies ... 251
Craniometry ................................................. 175 Development of Craniofacial Primordia ....... 251
Cephalometrics and Growth ........................ 182 Neural Crest Cells ........................................ 252
Standardizing the Cephalograms Ganglionic Placodal Cells ............................. 253
for Comparison ............................................ 186 Patterning Branchial Arches in Head ........... 254
Application of Cephalometrics Homeobox Genes ........................................ 254
in Growth and Development ....................... 187 Developmental Anomalies ............................ 255
Abnormal Growth Patterns .......................... 259
12. Growth Prediction ............................... 194
Need for Growth Prediction ........................ 194 16. Growth Considerations in Stability
Methods of Prediction .................................. 195 of Orthodontic Treatment .................... 262
Changes related to growth .......................... 262
13. Growth Rotations ................................. 220
Implant Radiography .................................... 220 17. Temporomandibular Joint ................... 266
Mandibular Growth Rotations ...................... 221 Anatomy of Temporomandibular Joint ........ 267
Bjork’s (1969) Classification ......................... 221 Embryology .................................................. 271
Bjork and Skeiller’s Method ........................ 223 Histology ...................................................... 272
 Contents xvii

Origin and Evolution ................................... 275 Mendelian Genetics ...................................... 317

Condylar Growth and Glenoid Modes of Inheritance ................................... 317
Fossa Displacement during Growth Multifactorial Inheritance .............................. 319
and in Malocclusion ..................................... 277 Twin Studies ................................................. 320
Limitations of Twin Studies .......................... 324
18. Myology and Neuromuscular Methods of Transmission
Reflexes ............................................... 279 of Malocclusion ............................................ 324
Muscle .......................................................... 279 Molecular Approach to Growth ................... 324
Skeletal Muscle ............................................. 280 Growth Factors ............................................. 324
Development of Muscle and Trilaminar Germ Disk ................................... 326
Muscle Changes During Growth .................. 283 Neural Crest Cells ........................................ 327
Skeletal Muscles in the The Role of Homeobox Genes ................... 328
Craniofacial Region ...................................... 284 Craniofacial Development ............................ 329
Form and Function ...................................... 285 Craniofacial Defects ...................................... 335
Research Methodology Regarding Future of Molecular Research
Form and Function—Factors Controlling in Craniofacial Growth ................................. 338
Facial Growth ............................................... 287
Reflex Control of Jaw Muscles .................... 291 21. Emotional Growth................................ 342
Schools of Psychology .................................. 342
19. Maturation of Orofacial Functions ....... 299 The Dynamics of Emotional
Respiration .................................................... 300 Development From Infant to Adult ............. 343
Swallowing or Deglutition ............................ 301 Theories of Emotional Development ........... 346
Mastication .................................................... 305 Habit Intervention and
Speech ......................................................... 308 Emotional Growth ....................................... 366
The Role of Malocclusion in
20. Genetics and Craniofacial Growth ...... 312
Psychological Development .......................... 367
DNA ............................................................. 313
Emotional Development and its Relation
Gene ............................................................ 314
to Cooperation in Treatment ....................... 371
Regulation of Gene Expression ................... 314
Up-regulation and Down-regulation ............ 315
Mutation ....................................................... 316 Index ........................................................... 373
 Biology of Bone
1 and Cartilage

CHAPTER OUTLINE matrix is mineralized by calcium phosphate in the form

• Classification of Bone of crystals very similar to hydroxyapatite. Bone is a tension
• Functions of Bone adapted tissue and tension on the periosteum will result
• Gross Structure of Long Bone in the differentiation of osteoblasts from the periosteal
• Types of Bone Tissue cells and leads to formation of new bone. On the other
• Molecular Structure of Bone hand, pressure on the periosteum will cause vascular
– The matrix of bone
occlusion and may produce bone resorption.
– Composition of bone
– Collagens
– Cells of bone CLASSIFICATION OF BONE
• Skeletogenesis/Bone Formation
– Membranous ossification Bones can be classified based on their position, shape,
– Endochondral ossification size, and structure.
– Initiation of calcification or Mineralization Based on location, bones can be classified as follows:
• Mechanisms of Bone Growth • Axial skeleton—Bones of the skull, vertebral column,
– Chondral growth sternum, and ribs.
– Sutural growth
– Periosteal growth
• Appendicular skeleton—Bones of the pectoral girdle,
– Remodeling pelvis girdle, and limbs.
• Cartilage • Acral skeleton—Part of the appendicular skeleton,
– Structure of cartilage including bones of the hands and feet.
– Lubrication mechanism of cartilage
– Cartilage replacement mechanisms Based on shape, bones can be classified as follows:
• Flat bone—Bones of the skull, sternum, pelvis, and
Bone is essentially a highly vascular, living, constantly ribs.
changing, mineralized connective tissue. Bone tissue is • Tubular bone
the structural material that gives the bones the strength • Long tubular bone, including bones of the limbs.
they require to act as levers for muscles, to give form • Short tubular bone, including bones of the hands
to the soft tissues of the body, and to provide protective and feet, such as the phalanges, metacarpals, and
cavities for the vital organs. However, bone tissue also metatarsals.
serves as a mineral bank that can be drawn upon in • Irregular bone—Bones of the face and vertebral
times of need. Morphologically bone tissue appears to column.
be under the control of bone cells. Its surfaces are • Sesamoid bone—Bones that develop in specific
enveloped by active and resting osteoblasts and tendons, the largest example of which is the patella.
osteoclasts, and it is permeated by an interconnected • Accessory bone or supernumerary bone—Extra
canalicular system in which osteocytes are found. Bone bones that develop in additional ossification centers
is a connective tissue distinguished by the fact that its or bones that failed to fuse with the main parts during
 2 Textbook of Craniofacial Growth

development (Accessory bones are common in the expanded end of bone, covered by articular cartilage.
foot and may be mistaken for bone chips or fractures). An epiphysis in a skeletally mature person consists of
abundant trabecular bone and a thin shell of cortical
Based on size, bones can be classified as follows:
bone. Although an epiphysis is present at each end of
• Long bone—Tubular in shape, with a hollow shaft
the long limb bones, it is found at only one end of the
and 2 ends, including bones of the limbs.
metacarpals (proximal first and distal second through
• Short bone—Cuboidal in shape, located only in the
the fifth metacarpals), metatarsals (proximal first and distal
foot (tarsal bones) and wrist (carpal bones).
second through fifth metatarsals), phalanges (proximal
FUNCTIONS OF BONE ends), clavicles, and ribs.
The epiphysis is the location of secondary ossification
Bones have the following main functions: centers during development. The structure of the
• Protection—Bones can serve to protect internal epiphysis is more complex in bones that are fused from
organs, such as the skull protecting the brain or the more than one part during development. Examples
ribs protecting the heart and lungs. include the proximal and distal ends of the humerus,
• Shape—Bones provide a frame to keep the body femur, and vertebrae. For instance, the proximal end
supported. of the humerus is developed from three separate
• Blood production—The marrow, located within the ossification centers, which later coalesce to form a single
medullary cavity of long bones and the interstices epiphyseal mass. In the proximal humeral epiphysis, one
of cancellous bone, produces blood cells in a process of the centers forms the articular surface, and the other
called haematopoiesis. two become the greater and lesser tuberosities. Carpal
• Mineral storage—Bones act as reservoir of minerals bones, tarsal bones, and the patella are also called
important for the body, most notably calcium and epiphysioid bones and are developmentally equivalent
phosphorus. to the epiphyses of the long bones.
• Helps in Movement—Bones, skeletal muscles,
tendons, ligaments and joints function together to Metaphysis: The metaphysis is the junctional region
generate and transfer forces so that individual body between the growth plate and the diaphysis. The
parts or the whole body can be manipulated in three- metaphysis contains abundant trabecular bone, but the
dimensional space. The interaction between bone cortical bone thins here relative to the diaphysis. This
and muscle is studied in biomechanics. region is a common site for many primary bone tumors
• Maintenance of Acid-base balance—Bone buffers the and similar lesions.
blood against excessive pH changes by absorbing or
Diaphysis: The diaphysis is the shaft of long bones and
releasing alkaline salts.
is located in the region between metaphyses, composed
• Detoxification—Bone tissues can also store heavy
mainly of compact cortical bone. The medullary canal
metals and other foreign elements, removing them
contains marrow and a small amount of trabecular bone.
from the blood and reducing their effects on other
tissues. These can later be gradually released for Physis (epiphyseal plate, growth plate): The physis is the
excretion. region that separates the epiphysis from the metaphysis.
• Transduction of sound—Bones are important in the It is the zone of endochondral ossification in an actively
mechanical aspect of hearing. growing bone or the epiphyseal scar in a fully grown
bone.
GROSS STRUCTURE OF LONG BONE
The gross structure of a long bone can be divided into TYPES OF BONE TISSUE
several regions.
Bone tissue can be classified in several ways, based on
Epiphysis: In the long bones, the epiphysis is the region texture, matrix arrangement, maturity, and develop-
between the growth plate or growth plate scar and the mental origin.
 Biology of Bone and Cartilage 3

Based on texture of cross sections, bone tissue can Based on developmental origin, bones can be
be classified as follows: classified as follows:
Compact bone (dense bone, cortical bone): Compact Intramembranous bone (mesenchymal bone):
bone is ivory like and dense in texture without cavities. Intramembranous bone develops from direct
It is the shell of many bones and surrounds the trabecular transformation of condensed mesenchyme. Flat bones
bone present in the center. Compact bone consists are formed in this way.
mainly of haversian systems or secondary osteons.
Intracartilaginous bone (cartilage bone, endochondral
Spongy bone (trabecular bone, cancellous bone): bone): Intracartilaginous bone forms by replacing a
Spongy bone is so named because it is sponge like with preformed cartilage model. Long bones are formed in
numerous cavities. It is located within the medullary cavity this way.
and consists of extensively connected bony trabeculae
The different parts of bone and their explanations
that are oriented along the lines of stress. In contrast
are as follows (Fig. 1.1):
to compact bone, complete osteons are usually absent
in spongy bone due to the thinness of the trabeculae. Periosteum: Periosteum is the highly vascular
Spongy bone is also more metabolically active than membranous tissue covering the bone that brings blood
compact bone because of its much larger surface area and lymph vessels, as well as nerves, to it . The functions
for remodeling. of periosteum include: bone nutrition, longitudinal and
transverse growth of bone, and its regeneration.
Based on matrix arrangement, bone tissue can be
classified as follows: Periosteum has two layers:
• External—fibrous; made of dense irregular connective
Lamellar bone (secondary bone tissue): Lamellar bone
tissue
is mature bone with collagen fibers that are arranged
• Internal—cellular (osteogenic); contains many
in lamellae. In contrast to spongy bone, in which lamellae
osteoblasts and blood vessels, some osteocytes as well.
are arranged parallel to each other, in compact bone,
the lamellae are concentrically organized around a Endosteum: It is a lining covering a bone from the
vascular canal, termed as haversian canal. marrow side, made of loose irregular connective tissue
Woven bone (primary bone tissue): Woven bone is
immature bone, in which collagen fibers are arranged
in irregular random arrays and contain smaller amounts
of mineral substance and a higher proportion of
osteocytes than lamellar bone. Woven bone is temporary
and is eventually converted to lamellar bone; this type
of bone is also pathologic tissue in adults, except in a
few places, such as areas near the sutures of the flat
bones of the skull, tooth sockets.
Based on maturity, bone tissue can be classified as
follows:
Immature bone (primary bone tissue): Immature bone
is woven bone.
Mature bone (secondary bone tissue): Mature bone is
characteristically lamellar bone. Almost all bones in adults Fig. 1.1: Schematic representation of structure
are lamellar bones. of a typical long bone
 4 Textbook of Craniofacial Growth

with osteoblasts and osteoclasts in addition to more matrix, all surrounding a hollow canal. These units of
common cell types of this tissue. It is a highly vascular structure, called osteons, run parallel in compact bone,
condensation of areolar tissue lining the various but form a looser and less-ordered network in spongy
medullary spaces bone. Compact bone forms in the perimeter of long
Compact bone (also known as cortical bone): Consists bone shafts, such as those of the legs and arms, where
of dense deposits of minerals—chiefly calcium phosphate stress forces tend to be in the same direction. In contrast,
and Type I collagen. These are arranged in concentric spongy bone is found in the ends of bones, where forces
circles around a central Haversian canal through which come from many different directions. Spongy bone also
blood, lymph vessels as well as nerves pass through. occurs where bone is not subject to significant stress.

Spongy bone (also known as trabecular or cancellous The Matrix of Bone (Fig. 1.2)
bone): The mineral deposits are arranged as a system
Two types of bone matrix are observed in the mature
of struts. Bone marrow fills the spaces between.
skeleton: hard compact cortical bone, found largely in
Bone marrow: Some bones, such as the femur, also the shafts of the long bones that surround the marrow
contain a central cavity filled with bone marrow. Bone cavities; and spongy or cancellous bone, which comprises
marrow contains the stem cells that give rise to all the a network of fine, interlacing partitions, the trabeculae,
types of blood cells. enclosing cavities that contain either hematopoietic or
fatty marrow. Cancellous bone is found in the vertebrae,
Epiphyseal plate: Until the end of puberty, this disk of
in the majority of the flat bones, and in the ends of the
cartilage produces more cartilage which then is
long bones.
converted into bone. In this way, the bone grows
lengthwise.
Cortical Bone
MOLECULAR STRUCTURE OF BONE Cortical bone represents nearly 80 percent of the skeletal
mass. It is also called compact bone, because it forms
Bone is created from osseous connective tissue. Like
a protective outer shell around every bone in the body.
other types of connective tissue, osseous tissue is
Cortical bone has a slow turnover rate and a high
composed of relatively sparse cells surrounded by an
resistance to bending and torsion. It provides strength
extracellular network, or matrix. Bone matrix is a tough,
resilient mixture of protein and minerals. Osteoblasts,
a type of bone cell, secretes proteins into the matrix,
which provide tensile strength (resistance to stretching
and twisting). The principal protein of the bone matrix
is collagen, which accounts for almost one-third of the
dry weight of bone. Most of the rest of the bone's weight
is due to the minerals of the matrix. These are mainly
calcium phosphate and calcium carbonate. Embedded
in the protein network, the minerals provide hardness
and compressive strength.
Bone cells remain alive and, like other cells in the
body, must be nourished by blood. In order to deliver
nutrients and to remove waste from the bone interior,
the hard, compact surface is pierced by "canals" through
which blood vessels can travel. Once inside, these canals
branch, allowing blood vessels to reach cells throughout
the bone. This canal system gives bone its characteristic Fig. 1.2: Organization of bone: depiction of the lamellar bone
appearance under the microscope, with bone cells in the shaft of a long bone, the Haversian systems, Volkmann's
embedded in concentric rings (lamellae) of calcified canal and inner and outer lamella
 Biology of Bone and Cartilage 5

where bending would be undesirable as in the middle constitutes about one-fifth of the weight of the matrix
of long bones. A closer view at this kind of bone (Fig. in mature bone; organic material forms 30-40 percent
1.2) will show a series of adjacent and overlapping bull’s and mineral salts 60-70 percent of the dry weight.
eye formations called osteons or Haversian systems. Each The main organic components are collagen,
osteon is composed of a central vascular channel mucopolysaccharides in combination with non-
surrounded by a kind of tunnel, called the Haversian collagenous proteins. The uncalcified organic matrix is
canal. The canal can contain capillaries, arterioles, called osteoid matrix. The organic part of matrix is mainly
venules, nerves and possibly lymphatics. Between each composed of Type I collagen. This is synthesised
osteon are interstitial lamellae (concentric layers of intracellularly as tropocollagen and then exported. It then
mineralized bone). Lamellar bone gets its strength from associates into fibrils. Also making up the organic part
its plywood-like construction: parallel layers of bone of matrix include various growth factors, the functions
alternate in orientation by 90 degrees. The Haversian of which are not fully known. Other factors present
canals communicate with the medullary cavity, with include glycosaminoglycans, osteocalcin, osteonectin,
spaces in spongy bone and with the surfaces of bone bone sialoprotein and Cell Attachment Factor. One of
by oblique or transverse channels termed Volkmann’s the main things that distinguishes the matrix of a bone
canals. from that of another cell is that the matrix in bone is
hard.
Trabecular or Cancellous Bone
Collagens
This kind of bone represents only 20 percent of the
skeletal mass, but constitutes 80 percent of the bone Collagen is the most abundant protein in mammals.
surface. Trabecular bone is less dense, more elastic and About one quarter of all of the protein in our body is
has a higher turnover rate than cortical bone. It is found collagen. Collagen is the main protein of connective
in the epiphyseal and metaphyseal regions of long bones tissue. It has great tensile strength, and is the main
and throughout the interior of short bones. Trabecular component of ligaments and tendons. It is responsible
bone constitutes most of the bone tissue of the axial for skin elasticity, and its degradation leads to wrinkles
skeleton: bones of the skull, ribs and spine. It is formed that accompany aging. Collagen also fills out the cornea
in an intricate and structural mesh. Trabecular bone where it is present in crystalline form. It is also used in
forms the interior scaffolding, which helps bone to cosmetic surgery, for example lip enhancement. The triple
maintain their shape despite compressive forces. helical structure of collagen was first proposed by
Trabecular bone is rigid but appears spongy, it is Ramachandran’s group from Madras. There are nearly
composed of bundles of short and parallel strands of 28 types of collagen described in literature. Over
bone fused together. The trabeculae are arranged in a 90 percent of the collagen in the body are Collagens
haphazard manner, but they are organized to provide I, II, III, and IV. The general functions of collagens are:
maximum strength similar to braces that are used to Collagen I—main component of bone and dentine,
support a building. The trabeculae of spongy bone follow Collagen II—main component of cartilage,
the lines of stress and can realign if the direction of stress Collagen III—main component of reticular fibers,
changes. The center of the bone contains red and yellow Collagen IV—forms the basement membrane.
marrow, bone cells and other tissues. A collagenous fiber is a bundle of many macrofibrils.
Each macrofibrils in turn is a bundle of numerous
Composition of Bone
microfibrils. The microfibril is composed of many
The bony tissue consists of ground substance or matrix tropocollagen helices. Each of these are assembled from
in which are embedded fibers and is impregnated with three polypeptide chains twisted together.
bone salts. The intercellular material, in which the cells Collagen has an unusual amino acid composition.
and fibers of connective tissue are embedded, is It contains large amounts of glycine and proline, as well
composed largely of glycosaminoglycans, metabolites, as two amino acids that are not inserted directly by
water, and ions are called as ground substance. Water ribosomes—hydroxyproline and hydroxylysine—the
 6 Textbook of Craniofacial Growth

former composing a rather large percentage of the total

amino acids. They are derived from proline and lysine
in enzymatic processes of post translational modification,
for which vitamin C is required. This is related to why
vitamin C deficiencies can cause scurvy, a disease that
leads to loss of teeth and easy bruising caused by a
reduction in strength of connective tissue due to lack
of collagen or defective collagen. The white collagen that
makes up the matrix of most connective tissue in
mammals consists of interwoven fibres of the protein
collagen. The collagen fibres consist of globular units of
the collagen sub-unit, the tropocollagen. Tropocollagen
sub-units spontaneously arrange themselves under
physiological conditions into staggered array structures
stabilized by numerous hydrogen and covalent bonds.
Tropocollagen sub-units are left-handed triple helices
where each strand is, further, a right-handed helix by
itself. Thus, tropocollagen may be considered to be a Figs 1.3A to E: The structure of collagen on several length
coiled coil. Each chain is left handed helix and the scales. (A to C) The three subunits of collagen coil together
wrapping is right-handed. into a triple helix, with the H side group of glycine fitting into
the center of the molecule. Each subunit contains 1050 amino
Another rare feature of collagen is its regular
acids, and when wound the helix is about 300 nm long. (D
arrangement of amino acids in each of the alpha chains and E) In a collagen fibril, adjacent collagen molecules are
of the collagen sub-units (Figs 1.3A to E). The sequence staggered with their ends 67 nm apart, producing visible
generally follows the pattern Gly-X-Y, where Gly for striations in stained collagen
glycine, and X and Y for any amino acid residues. Most
of the times, X is for proline and Y is for hydroxyproline. • Peptide chains are sent into the lumen of the RER.
There are very few other proteins with such regularity. • Signal Peptides are cleaved inside the RER and the
The inordinate number of Gly residues allows the chains are now known as procollagen.
otherwise sterically disallowed, tight coiling of each of • Hydroxylation of lysine and proline amino acids
the alpha chain subunits of tropocollagen, where there occurs inside the lumen. This process is dependent
is a rise per turn of just 0.3 nm as opposed to the .36 on Ascorbic Acid (Vitamin C) as a cofactor.
nm of a regular Alpha helical coil. Hydroxylysine and • Glycosylation of specific hydroxylated amino acid
hydroxyproline play important roles in the stabilization occurs.
of the tropocollagen globular structure as well as the • Triple helical structure is formed inside the RER.
final fiber shaped structure by forming covalent bonds. • Procollagen is shipped to the golgi apparatus, where
The resulting structure is called a collagen helix. it is packaged and secreted by exocytosis.
The synthesis of type I collagen takes place in the
following way (Figs 1.4A and B): Outside the Cell
• Registration peptides are cleaved and tropocollagen
Inside the Cell is formed by procollagen peptidase.
• Three peptide chains are formed (Two alpha-1 and • Multiple tropocollagen molecules form collagen fibrils,
one alpha-2 chain) in ribosomes along the Rough and multiple collagen fibrils form into collagen fibers.
Endoplasmic Reticulum (RER). These peptide chains • Collagen is attached to cell membranes via several
(known as preprocollagen) have registration peptides types of protein, including fibronectin and integrin.
on each end; and a signal peptide is also attached The collagen fiber is clearly identified in the electron
to each. microscope by the banded pattern which gets repeated
 Biology of Bone and Cartilage 7

Figs 1.4A and B: Synthesis of collagen (Klug and Cummings, 1997)

regularly at 64 nm intervals. The protein carbohydrate polysaccharide side chains, glycosaminoglycans. The
complexes of bone are of two types, proteoglycans and glycosaminoglycans consists of regularly repeating units
glycoproteins. These substances contribute to the physical of two sugars.
characteristics of bone and cartilage. Proteoglycans The inorganic part is mainly crystalline mineral salts
consists of a protein chain or core to which is attached and calcium, phosphate, hydroxyl ions, carbonate and
 8 Textbook of Craniofacial Growth

water which is present in the form of hydroxyapatite. layer over bone surfaces on which matrix is being formed.
The mineral is a basic calcium phosphate, being an The cells are polarized, in that new osteoid, referred to
apatite, hydroxylapatite [Ca10(PO4)6(OH)2]. as an osteoid seam, is deposited along the surface
adjacent to bone. The deeper portion of the osteoid
Cells of Bone (Fig. 1.5) seam undergoes mineralization along the so-called
Osteoblasts, osteocytes, osteoclasts, and osteogenic or mineralization front. The bone is essentially enveloped
osteoprogenitor cells are found in developing bone, by the osteoblasts, since the cells are in close contact
regardless of the site of formation. with one another and tight junctions and gap junctions
have been observed. Thus, the osteoblastic layer controls
Osteoblasts the transport of materials from the extracellular space
Osteoblasts take origin from poorly differentiated to the osteoid seam and mineralization front.
mesenchymal cells; residing in the internal layer of Ultrastructurally, osteoblasts (Fig. 1.6) feature a
periosteum, during bone development, osteoblasts are complement of organelles characteristic of cells actively
on the periosteal surface and around interosseous blood involved in protein synthesis. They have abundant
vessels; these cells are cuboidal, columnar and polygonal endoplasmic reticulum and numerous ribosomes, and
in shape, have a well-developed rough endoplasmic the Golgi apparatus and mitochondria are quite
reticulum. Osteoblasts are the cells responsible for the prominent. Procollagen molecules are produced by the
formation and organization of the extracellular matrix ribosomes and extruded into the extracellular space, but
of bone and its subsequent mineralization. They are only along the surface that faces bone. Proteolysis and
derived from mesenchymal precursor cells in marrow polymerization within the extracellular space results in
that have the potential to differentiate into fat cells, the formation of collagen fibrils. The combination of these
chondrocytes or muscle cells (Owen & Ashton, 1986; intracellular and extracellular events leads to the
Beresford, 1989). The origin of osteoblastic cells in the production of the osteoid seam. Most of the
developing long bones is less well defined. One proteoglycans are packaged in the Golgi apparatus, and
hypothesis is that the osteoblasts are derived from blood- vesicles containing these products then migrate to the
borne elements. This view is supported by evidence that surface of the cell and release their contents by exocytosis.
cells in empty lacunae express type I collagen mRNA Membrane-bound vesicles containing amorphous
and are morphologically similar to osteoblasts, but unlike calcium phosphate are extruded from the plasma
hypertrophic chondrocytes do not express type X membrane of the osteoblast into the extracellular space.
collagen mRNA. The alternative view is that osteoblasts It appears that these vesicles induce and actually activate
are derived from hypertrophic chondrocytes, since type crystal formation. Alkaline phosphatase, which is
I collagen has been immunolocalized in apparently intact produced by the osteoblast, is thought to act as a
lacunae (don der Mark, 1989). Osteoblasts form a cell pyrophosphatase and may be involved in the initiation

Fig. 1.5: Diagrammatic representation of cells present in bone

 Biology of Bone and Cartilage 9

Osteocytes
A mature form of osteoblasts, they lie in lacunae within
a bone and extend protoplasmic processes into small
canaliculi in the intercellular matrix. Approximately
10 percent of the osteoblastic population become
enclosed in the developing matrix and are then referred
to as osteocytes. Osteocytes have structural features very
similar to osteoblasts when they are on the surface of
the matrix, but the endoplasmic reticulum may not be
so profuse. As the cells become more deeply embedded
in mineralized bone matrix, their cytoplasmic volume
is reduced, as is their complement of cytoplasmic
organelles. Osteocytes have cytoplasmic processes that
extend into the surrounding matrix for some distance
and fill most of the canaliculi in which they are contained.
The processes of osteocytes contact processes from other
osteocytes and osteoblasts on the surface, forming tight
junctions. This interconnection of osteoblastic lining cells
with the osteocytes deep within bone regulates the flow
of mineral ions from the extracellular fluid through the
Fig. 1.6: Osteoblasts lining a trabeculum of cancellous bone. osteoblast to the osteocytes, from the osteocytes to the
The cytoplasm contains rough endoplasmic reticulum (ER)
extracellular fluid surrounding them, and finally from
and scattered mitochondria (M). Golgi complexes (G) are well
developed and have cisternae distended with fibrillar this fluid to the mineralized bone matrix. Thus, the large
material. Cytoplasmic processes of osteoblasts (arrows) surface area provided by the osteocytic population results
extend into adjacent osteoid (O), which is interposed between in a regulatory mechanism for the exchange of mineral
the osteoblasts and underlying mineralized matrix of woven ions between the extracellular fluid and bone by means
bone (B). Osteoblast nuclei are shown (N). (original
of the canalicular system. Osteocytes appear to be
magnification x 6420) [ Fetter AW. Electron microscopic
evaluation of bone cells in pigs with experimentally induced essential to the maintenance of bone, since when the
Bordetella rhinitis (turbinate osteoporosis). Am J Vet Res cell dies, the matrix around it eventually is removed.
1975;36(1):15-22] Osteocytes have also been shown to act as mechano-
sensory receptors—regulating the bone's response to
stress and mechanical load. They are mature bone cells.
of the mineralization process. The transformation of
Osteoclasts
amorphous calcium phosphate to crystalline
hydroxyapatite appears to take place both inside and Osteoclasts are large, multinucleated cells located on
outside the matrix vesicles. When crystals formed within bone surfaces in what are called Howship's lacunae or
the vesicle contact the membrane of the vesicle, the resorption pits. These lacunae, or resorption pits, are
membrane ruptures. The crystals, which are then left behind after the breakdown of bone and often
exposed to a supersaturated solution, induce present as scalloped surfaces. Osteoclasts are
precipitation over the entire matrix surface. macrophages of bone tissue, blood monocytes being
The principal products of the mature osteoblast are their precursors; large multinucleated cells; a zone of
type I collagen (90% of the protein in bone), the bone cytoplasm adjacent to osseous surface is referred to as
specific vitamin-K dependent proteins, osteocalcin and ruffled border, multiple cytoplasmic processes and
matrix Gla protein, the phosphorylated glycoproteins lysosomes are found in them. The size of osteoclasts may
including bone sialoproteins I and II, osteopontin and be up to 200,000 μm3 with up to 100 nuclei. Functions
osteonectin, proteoglycans and alkaline phosphatase. of osteoclasts include destruction and resorption of bone
 10 Textbook of Craniofacial Growth

fibers and ground substance. Because the osteoclasts are and reduce ruffled border size. Glucocorticoids (GCs)
derived from a monocyte stem-cell lineage, they are are another class of systemic agents that cause bone loss.
equipped with engulfment strategies similar to circulating Although this may be due to their inhibition of intestinal
macrophages. Osteoclasts mature and/or migrate to calcium absorption and the induction of secondary
discrete bone surfaces. Upon arrival, active enzymes, such hyperparathyroidism, GCs also have direct actions on
as tartrate resistant acid phosphatase, are secreted against bone cells. These direct effects on bone are believed to
the mineral substrate. be via the local regulation of cytokine and prostaglandin
Osteoclasts are polarized cells, having a ruffled border production. Prostaglandins are locally produced by most
region of the cell membrane that is surrounded by an cells in the body, and have been shown to have direct
organelle-free region, or 'clear zone', and they adhere effects on osteoclasts and their precursors, inhibiting
to the bone surface via integrins, which are specialized bone resorption by mature osteoclasts and increasing
cell surface receptors. Osteoclastic bone resorption the formation of their precursors.
initially involves mineral dissolution, followed by There is no clear evidence as to the fate of osteocytes
degradation of the organic phase. These processes take when bone matrix is resorbed. It has been suggested
place beneath the ruffled border and depend on that osteoclasts can undergo fission into mononuclear
lysosomal enzyme secretion and an acid microenviron- cells on the endosteal bone surface and that these
ment. A pH gradient across the ruffled membrane is the mononuclear cells undergo a modulation of cell function
consequence of active transport mechanisms such as to osteoblasts and then osteocytes.
Na+/H+ exchange, ATP-dependent proton pumps, and
the enzyme carbonic anhydrase. Osteoclasts actively Osteogenic Cells
synthesize lysosomal enzymes, in particular the tartrate
Osteogenic cells are derived from undifferentiated
resistant isoenzyme of acid phosphatase (TRAP) (used
mesenchymal cells, which are also believed to give rise
as a marker of the osteoclast phenotype), and cysteine-
to the formed hematopoietic elements. There is evidence
proteinases such as the cathepsin S that are capable of
that bone marrow contains both predetermined
degrading collagen. Lysosomal enzymes are only released
osteoprogenitor cells and cells that will form bone in the
at the ruffled border region of the osteoclast cell
presence of a suitable inducer.
membrane. Other cells in bone, in particular the
osteoblast, may be involved in degrading the organic
SKELETOGENESIS/BONE FORMATION
non-mineralized phase from bone surfaces. In vitro
studies have shown that removal of non-mineralized Bone formation occurs by three co-ordinated processes:
organic matrix is necessary before mineralized matrix the production and the maturation of osteoid matrix or
may be resorbed by isolated osteoclasts (Chambers & skeletogenesis, and subsequent mineralization of the
Fuller, 1985). matrix. In the embryo, bone tissue arises through
Systemic agents, important in regulating osteoclastic two processes, intramembranous ossification and
bone resorption, are parathyroid hormone (PTH), 1,25 endochondral ossification. In intramembranous
di-hydroxy vitamin D3[1,25(OH)2D3] and calcitonin. ossification, bone is formed directly from mesenchymal
PTH and 1,25(OH) 2 D 3 are unable to stimulate tissue. The flat bones of the skull and face, the mandible
osteoclastic bone resorption in vitro in the absence of and the clavicle develop in this manner. In endochondral
osteoblastic cells. This gave rise to the idea that these ossification, a cartilage model of the bone is formed first,
agents stimulate osteoclasts to resorb bone via a ‘coupling’ and is later replaced by bone. The weight-bearing bones
factor. Osteoclasts do not have receptors for of the axial skeleton and the bones of the extremities
1,25(OH)2D3, and until recently were not believed to (most of the skeleton) develop in this manner.
have PTH receptors, although the functional significance The first bone to arise, whether from mesenchyme
of PTH receptors on osteoclasts remains to be or from cartilage (or in fracture repair postnatally), is
established. Osteoclasts have calcitonin receptors and this in the form of spicules. These first spicules are made of
inhibitor of bone resorption acts directly on the osteoclast immature bone, also called woven bone. In immature
to reduce cellular motility, retract cytoplasmic extensions bone, the collagenous lamellae are not arranged in
 Biology of Bone and Cartilage 11

parallel or concentric arrays (as in mature spongy and bone is to be formed. The tissue in this area becomes
compact bone, respectively), but are randomly oriented more vascularized, and the mesenchyme cells begin to
and loosely intertwined (hence woven). Immature bone differentiate into osteoblasts, which secrete the collagen
also has more ground substance than mature bone. and ground substance (proteoglycans) of bone matrix
Consequently, immature and mature bone (Fig. 1.7) (collectively called osteoid). The osteoblasts maintain
show different staining characteristics, immature bone contact with one another via cell process. The osteoid
stains more with hematoxylin and mature bone more becomes calcified with time, and the processes of the
with eosin. The spicules of immature bone are cells (called osteocytes when they are surrounded with
remodeled. The remodeling process can eventually give matrix) become enclosed in canaliculi. Some of the
rise to more spongy bone or to compact bone. The mesenchymal cells surrounding the developing bone
remodeling of bone continues throughout life (remember spicules proliferate and differentiate into osteoprogenitor
those interstitial lamellae in compact bone represent cells. Osteoprogenitor cells in contact with the bone
former osteons). Immature bone is the predominant spicule become osteoblasts, and secrete matrix, resulting
bone in the developing fetus. In the adult, most immature in appositional growth of the spicule. Intramembranous
bone is replaced by mature bone, but immature bone ossification begins at about the eighth week in the human
is seen where bone is being remodelled or repaired, and embryo.
in certain specific areas, such as the alveolar sockets of The sequence of events which take place in
the oral cavity. When bone matrix is first secreted, it is membranous ossification are as follows:
not yet mineralized and is called osteoid. As mentioned • Increased vascularity of tissue.
above, osteoblasts also bring about the mineralization • Active proliferation of mesenchymal cells. The
of bone. mesenchymal cells give rise to osteogenic cells, which
develop into osteoblasts.
• Osteoblasts begin to lay down osteoid. Osteoid is the
Membranous Ossification (Fig. 1.8)
organic part of bone without the inorganic
Also called as direct ossification/intramembranous constituent.
ossification. The first step in intramembranous ossification • Osteoblasts either retreat or become entrapped as
is the aggregation of mesenchymal cells in the area where osteocytes in the osteoid.

Fig. 1.7: Numerous osteocytes (ocy) are seen enclosed within

the spicule, and most of the periphery is lined by osteoblasts
(ob). (A characteristic feature of immature bone is a greater
abundance of cells than in mature bone). Several developing Fig. 1.8: Intramembranous Ossification (Source: Gartner
blood vessels (bv) are seen in the mesenchyme and Hiatt, Color Textbook of Histology)
 12 Textbook of Craniofacial Growth

• The osteoid calcifies to form spicules of spongy bone. Sometimes, during the growth of this cartilage model
The spicules unite to form trabeculae. The inorganic (starting at about week 12 in the human fetus), some
salts carried in by the blood vessels supposedly bring of the inner perichondrial cells begin to give rise to
about calcification. The salts are deposited in an osteoblasts instead of chondroblasts (As a result, the
orderly fashion as fine crystals (hydroxyapatite former perichondrium is now called the periosteum).
crystals) intimately associated with the collagenous In long bones, this process begins at the mid-region of
fibers. These crystals are only visible with the electron the bone. The newly formed osteoblasts secrete osteoid,
microscope. forming a bone collar around the cartilage model.
• Bone remodeling occurs. Periosteum and compact Therefore the very first bone that is formed during
bone are formed. endochondral ossification is considered to arise by
Intramembraneous bone formation occurs on the intramembranous ossification.
outer surface of periosteum, the Endosteum, on the Development of long bones begins with condensation
surfaces of trabeculae of cancellous bone and at the edges of the mesenchyme to form a cartilaginous model of
in specialized structures called sutures. the bone to be formed (Fig. 1.9). Mesenchymal cells
undergo division and differentiate into prechondroblasts
Endochondral Ossification and then into chondroblasts. These cells secrete the
Endochondral ossification is the replacement of hyaline cartilaginous matrix. Like osteoblasts, the chondroblasts
cartilage by bone. It is usually evident in the long bone, become progressively embedded within their own
but the growth of cranial base synchondroses and matrix, where they lie within lacunae, and they are then
condylar cartilage also serves the purpose equally. called chondrocytes. Unlike osteocytes however,
Endochondral ossification also begins with the chondrocytes continue to proliferate for some time, this
aggregation of mesenchyme cells, but these differentiate being allowed in part by the gel-like consistency of
into chondroblasts which secrete hyaline cartilage matrix. cartilage. At the periphery of this cartilage (the
The cartilage is secreted in the general shape of the bone perichondrium), the mesenchymal cells continue to
that it will become, and grows by both interstitial (mostly proliferate and differentiate. This is called appositional
in length) and appositional (mostly in width) growth. growth. Another type of growth is observed in the

Fig. 1.9: Postnatal development of long bones. The four layers namely resting or zone of reserve cells, zone of
hyperplasia or proliferation, zone of hypertrophy and zone of matrix calcification are seen
 Biology of Bone and Cartilage 13

cartilage by cell proliferation and synthesis of new matrix Secondary ossification centers begin to form at the
between the chondrocytes (interstitial growth). epiphyseal ends (Fig. 1.10) of the cartilaginous model,
Beginning in the center of the cartilage model, at and by a similar process, trabecular bone and a marrow
what is to become the primary ossification center, space are formed at these ends. Between the primary
chondrocytes differentiate and become hypertrophic. and secondary ossification centers, epiphyseal cartilage
During this process, hypertrophic cells deposit a (growth plates) remain until adulthood. The continued
mineralized matrix, where cartilage calcification is initiated differentiation of chondrocytes, cartilage mineralization
by matrix vesicles. Once this matrix is calcified, it is partially and subsequent remodeling cycles allow longitudinal
resorbed by osteoclasts. After resorption and a reversal bone growth to occur, such that as new bone is formed,
phase, osteoblasts differentiate in this area and form a the bone will reach its final adult shape. There is, however,
layer of woven bone on top of the remaining cartilage. a progressive decrease in chondrocyte proliferation so
This woven bone will later be remodeled into lamellar that the growth plate becomes progressively thinner,
bone. allowing mineralization and resorption to catch up. It
The embryonic cartilage is avascular. During its early is at this point that the growth plates are completely
development, a ring of woven bone is formed at the remodeled and longitudinal growth is arrested.
periphery by intramembranous ossification in the future The growth plate demonstrates, from the epiphyseal
midshaft area under the perichondrium (which becomes area to the diaphyseal area, the different stages of
periosteum). Following calcification of this woven bone, chondrocyte differentiation involved in endochondral
blood vessels, preceded by the osteoclasts entering the bone formation (see Fig. 1.9). Firstly, a proliferative zone,
primary ossification center, will penetrate this bone and where the chondroblasts divide actively, forming
the calcified cartilage, forming the blood supply which isogenous groups, and actively synthesizing the matrix.
will allow seeding of the hematopoietic bone marrow These cells become progressively larger, enlarging their
and invasion of osteoclasts to resorb the calcified lacunae in the pre-hypertrophic and hypertrophic zones.
cartilage. Lower in this area, the matrix of the longitudinal cartilage

Fig. 1.10: Prenatal long bone development: Steps in the conversion of cartilage anlage to a mature long bone.
Primary and secondary ossification centers are evident
 14 Textbook of Craniofacial Growth

septa selectively calcifies (zone of provisional calcification). Table 1.1: Mode of ossification
The chondrocytes become highly vacuolated and then of the bones of the skull
die through programmed cell death (apoptosis). Once Membrane Cartilage
calcified, the cartilage matrix is resorbed, but only partially,
Maxilla Ethmoidal bone
by osteoclasts, leaving the calcified longitudinal septae, Zygomatic bone Nasal concha
and blood vessels appear in the zone of invasion. After Palatine bone Sphenoidal base
resorption, osteoblasts differentiate and form a layer of Vomer Petrous part of temporal bone
woven bone on top of the cartilaginous remnants of the Lacrimal bone Occipital basalis
Frontal bone Malleus
longitudinal septa. Thus, the first ARF sequence is
Parietal bone Incus
complete: the cartilage has been remodeled and replaced Squamous and petrous part
by woven bone. The resulting trabeculae are called the of temporal bone Stapes
primary spongiosum. Still lower in the growth plate, this Squamous occipitalis
woven bone is subjected to further remodeling (a second Os Sphenoidal
ARF sequence) in which the woven bone and the • Lamina medialis
• Apex of ala major
cartilaginous remnants are replaced with lamellar bone,
resulting in the mature trabecular bone called secondary
spongiosum.
Chondrocyte differentiation is regulated by a number local concentration of phosphate to the level where
of factors which have recently been described. The first calcium phosphate would precipitate. The second
factor shown to control chondrocyte differentiation was concept "seeding concept" suggests that a crystalline
parathyroid hormone related peptide (PTHrP). This substance by virtue of its structure is similar to
factor prolongs chondrocyte proliferation, and in PTHrP hydroxyapatite to induce the aggregation of calcium
knockout mice, the main phenotype is bone shortening and phosphate ions. The body fluids which are
caused by premature chondrocyte hypertrophy. Targeted supersaturated would then form a complete crystal by
overexpression of PTHrP results in the opposite oriented growth or epitaxy. The seed may be organic
phenotype, with prolonged delay in chondrocyte or crystalline in nature. Electron microscopic studies have
maturation. PTHrP is part of a genetic signaling cascade, shown that the earliest resolvable mineral particles that
where not only is it regulated by factors expressed earlier can be seen are associated with the periodic banding
in chondrocyte differentiation, such as Indian hedgehog of the collagen fibers. The third concept states that
(Ihh), but it also regulates chondrocyte differentiation initiation of calcification occurs by the production of so
itself, and alters gene expression in more mature called "matrix vesicles". The vesicles are produced by
chondrocytes. Other factors which regulate chondrocyte the cells of calcifying systems by a process of budding
differentiation include the FGFs and bone from the cell membrane. Vesicles are produced with the
morphogenetic proteins (BMPs). Table 1.1 shows the ability to form apatite crystals internally which eventually
bones of skull and their modes of ossification. rupture the enclosing membrane and are exposed to
the tissue fluids resulting in further crystallite growth.
Initiation of Calcification or Mineralization These vesicles are identified in all calcifying tissues except
enamel.
The matrix is initially laid down as unmineralized osteoid
(manufactured by osteoblasts). Mineralization involves Factors Influencing Mineralization
osteoblasts secreting vesicles containing alkaline
phosphatase. This cleaves the phosphate groups and acts Local Factors
as the foci for calcium and phosphate deposition. The Collagen—Collagen provides an oriented support for
vesicles then rupture and act as a centre for crystals to newly formed mineral crystals. The specific longitudinal
grow on. The exact mechanism of calcification is still under and lateral staggering of the collagen molecules in the
debate. Robinson noticed that alkaline phosphatase was fibril results in holes and pores in which nucleation, crystal
always present at sites of calcification and suggested that growth, secondary nucleation and multiplication of the
this enzyme hydrolyzed phosphate esters to increase the solid phase can occur.
 Biology of Bone and Cartilage 15

Noncollagenous molecules • Extracellular Matrix Secretion: In this process, there

Name Composition Possible Function
is increase in size because of the secretions of the
cells, into the extracellular matrix.
Osteopontin Phosphoprotein Inhibits crystal growth
Osteonectin Phosphoprotein Inhibits crystal growth
In hard tissues like bone and teeth, the extracellular
Bone sialo- Phosphorylated Nucleator for mineralization material gets mineralized. Because of mineralization,
protein glycoprotein interstitial growth is not possible in hard tissue.
GLA Protein Protein and γ-carboxy Regulator of crystal growth Hyperplasia, hypertrophy and extracellular matrix
glutamic acid
Biglycan and Chondroitin sulfate Removed at mineralization
secretion all occur only on the surface. New cell formation
Decorin and proteoglycans front to permit mineralization takes place in the periosteum, the soft tissue membrane
Phospholipids Calcium binding at that covers the bone. Therefore, bone growth takes place
mineralization front only by "Surface deposition of bone". There is addition
Pyrophosphate Inhibitor of calcification
of fresh bone to the surface of existing bone.
Post natal growth of bone takes place in the following
Growth Factors three ways:
FGF Increase osteoblastic precursor population and also • Chondral growth, achieved by interstitial growth of
increase collagen synthesis cartilage originating in cartilage. Example includes
IGF Increase bone cell proliferation and total protein
synthesis
synchondroses.
TGF, PGDF : Increase proliferation of osteoprogenitor and total • Sutural growth is appositional growth and occurs in
protein synthesis the skull and facial sutures on the edge of bones.
Interleukin 1 : At low doses, it stimulates collagen synthesis but is • Periosteal growth which is also appositional and occurs
inhibitor in higher concentrations
in the periosteum. Periosteal growth unlike the
chondral and sutural growth continues into advanced
Tumor necrosis factor: stimulate proliferation and age.
collagen synthesis in preosteoblasts.
Chondral Growth
Systemic factors: Parathyroid hormone, 1, 25 - dihydroxy
vitamin D3, estrogen, insulin, etc. exerts effect on bone Cartilage occurs at the base of skull in the form of
formation. synchondroses, nasal septum, symphyseal and condylar
cartilage. Synchondroses growth continues until the bone
Role of alkaline phosphatase: Alkaline phosphatase is an
is ossified. The significance of synchondroses are as
ecto enzyme produced by osteoblasts that is a useful
follows:
marker of osteoblast activity. It has a clear function—
• The organic matrix in cartilage is not normally calcified
hydrolyzing phosphate ions from organic radical at an
and because the tissue is avascular, metabolites must
alkaline pH. Its precise role in mineralization is not clear.
enter and leave by simple diffusion. As there are no
Hydroxyapatite crystals in contact with serum or tissue
blood vessels to occlude, cartilage can be utilized in
fluids are prevented from growing larger because
areas of the skeleton which are subjected to pressure.
pyrophosphate ions are deposited on their surfaces
• Also cartilage like soft tissue has interstitial as well as
inhibiting further growth. Alkaline phosphatase activity
appositional growth. Interstitial growth is possible
breaks down pyrophosphate thereby permitting crystal
because the matrix is not calcified and can therefore
growth to proceed.
expand to accommodate the chondrocytes resulting
from cell division.
MECHANISM OF BONE GROWTH
• The physical and biological properties of cartilage are
There are three basic mechanisms by which growth takes ideal for flexible support and growth necessary during
place at the cellular/tissue level. They are: skeletogenesis.
• Hyperplasia: Growth due to increase in number of • The growth of cartilage is also bidirectional unlike
cells. the periosteal growth which is unidirectional.
• Hypertrophy: Growth due to increase in size of the The growth and activity of synchondroses is controlled
cells. by growth hormones (STH). Excessive production of
 16 Textbook of Craniofacial Growth

STH results in lengthening of cranial base, while under

production leads to shortening of base of skull and hence
leads to underdevelopment of midface. The importance
of nasal septum is disputable. The cartilage at the
symphysis menti retains its growth activity up to first year
of life whereas condylar cartilage growth activity is traced
up to maturity.

Sutural Growth
Sutural growth occurs due to osteoblasts and is similar
to periosteal growth, the difference being that bone
apposition takes place at the edges of bone. The histology
of suture shows, a cellular osteoblastic layer bordering
the bone, a fibrous layer and a middle zone (Fig. 1.11).
The middle zone contains numerous blood vessels and
connects both the fibrous layer to one another. The active
growth of suture is found only at the bone edges. Fig. 1.11: A schematic illustration of the two differing views
on the structure of the suture. A represents the three-layer
Premature fusion (synostosis) of suture leads to skull concept; B, the five-layer concept
deformities. Table 1.2 shows the different deformities
produced due to premature fusion of craniofacial sutures.
The various bony joints are given as follows: Table 1.2: Premature closure of various
Bony joints: sutures and their effects
• Suture: Type of fibrous joint in which the opposed Sutures Skull deformity
surfaces are firmly united.
Sagittal suture Scaphocephaly
• Symphysis: Two bony surfaces are firmly united by Symmetric fusion of
a plate of fibro cartilage. coronal suture Oxycephaly (Tower skull)
• Synostosis: Union of adjacent bones by osseous Asymmetric fusion of
matter. coronal suture Plagiocephaly
• Syndesmosis: Fibrous junction in which the Metopic suture Trigonocephaly (wedge skull)
intervening fibers form an interosseous membrane.
• Synchondrosis: A cartilaginous joint that is usually
Periosteal Growth
temporary and gets converted into bone in adult life.
Periosteum controls the resorption and deposition of the
Scott and Dixon (1978) have summarized the
bone during maturity. The growth direction of periosteal
craniofacial sutures system as follows:
growth is on one side only and bone growth or
• Lambdoid suture system divides the occipital
deposition takes place only on the surface.
squamous from the parietal and temporal bones.
Growth from the suture affects mainly the back of
Remodeling
skull.
• Coronal suture promote longitudinal growth of the Bone remodeling is the process by which bone is turned
skull. over; it is the result of the activity of the bone cells at
• Craniofacial and maxillofacial suture system the surfaces of bone, mainly the endosteal surface (which
contribute to forcing the middle face downwards and includes all trabecular surfaces). Remodeling is
forwards. traditionally classified into two distinct types: Haversian
• Sagittal suture is responsible for growth in width of remodeling within the cortical bone and endosteal
the cerebral and facial skull. remodeling along the trabecular bone surface. This
 Biology of Bone and Cartilage 17

distinction is more morphological than physiological

because the Haversian surface is an extension of the
endosteal surface and the cellular events during these
two remodeling processes follow exactly the same
sequence.
Bone formation and bone resorption do not occur
along the bone surface at random: they are co-ordinated
as part of the turnover mechanism by which old bone
is replaced by new bone. In the normal adult skeleton,
bone formation only occurs, for the most part, where
bone resorption has already occurred. This basic principle
of cellular activity at the remodeling site is the Activation-
Resorption-Formation (ARF) sequence (Fig. 1.12).
Under some signal, a locally acting factor released
by lining cells, osteocytes, marrow cells, or in response Fig. 1.12: The ARF sequence of bone remodeling
to bone deformation or fatigue-related microfracture,
a group of preosteoclasts are activated. These
mononuclear cells attach to the bone via avb3 integrins
and fuse to form a multi-nucleated osteoclast which will,
in a definite area of the bone surface, resorb the bone
matrix. After resorption of the bone, and osteoclast
detachment, uncharacterized mononuclear cells cover
the surface and a cement line is formed. The cement
line marks the limit of bone resorption, and acts to cement
together the old and the new bone. This is termed the
reversal phase, and is followed by a period of bone Fig. 1.13: Diagrammatic representation of structure of
formation. Preosteoblasts are activated, proliferate and cartilage proteoglycans
differentiate into osteoblasts, which move onto the bone
surface, forming an initial matrix (osteoid), which hexosamines). In cartilage, the GAGs attached to the
becomes mineralized after a time lag (the osteoid core proteins are chondroitin sulfate and keratan sulfate.
maturation period). The basic remodeling sequence is The proteoglycans themselves are attached, by special
therefore Activation-Resorption-Formation; it is linker proteins to long, rigid molecules of hyaluronic acid
performed by a group of cells called the Basic Multicellular (HA). HA itself is a GAG, but is composed of several
Unit (BMU). The complete remodeling cycle takes about thousand disaccharide units, rather than several hundred
3 months in humans. or less, as are other GAGs. About eighty proteoglycans
are attached to one molecule of HA. The repeating units
CARTILAGE
of chondroitin sufate are D-glucuronic acid and N-
Cartilage is a solid connective tissue that is to a certain acetylgalactosamine-(4 or 6)-sulfate. The repeating units
extent pliable, making it resilient. These characteristics of keratan sulfate are galactose or galactose 6-sulfate
of cartilage are due to the nature of its matrix. The and N-acetylglucosamine 6-sulfate. The repeating units
ground substance of cartilage is rich in proteoglycans of hyaluronic acid are D-glucuronic acid and N-
(Fig. 1.13) consisting of a core protein with numerous- acetylglucosamine. The properties of proteoglycans in
about 100-glycosaminoglycans (GAGs) attached in cartilage can be summarized as follows:
bottle-brush fashion around it. GAGs are made of • Basic unit: glycosaminoglycans (GAGs) which are
repeating units of disaccharides, one of which is always mutually repelled between neighboring GAGs.
a glycosamine (hence the name) such as glucosamine • Proteoglycan: hyaluronic acid, link protein, the GAG
or galactosamine (Glycosamines are also called chains: 200-400 nm in length.
 18 Textbook of Craniofacial Growth

• Chondroitin sulfate chains (CS): decrease with aging.

• Keratan sulfate chains (KS): increase with develop-
ment and aging.
The matrix also has collagen fibers, but these are of
a finer nature (collagen Type II vs. collagen Type I) than
the collagen fibers in most other connective tissues. The
macromolecules are bound to the thin collagen fibres
by electrostatic interactions and cross-linking
glycoproteins. Properties of collagen fibers in articular
cartilage:
• biological unit: tropocollagen
• mechanical properties: tensile stiffness and strength
Fig. 1.14: Arrangement of collagen in cartilage
• distribution of collagen in articular cartilage (Fig. 1.14)
– superficial tangential zone: parallel to the articular
surface. interconnecting sheets of elastic material. This gives elastic
– middle zone: randomly distributed. cartilage an elasticity which is not present in hyaline
– deep zone: perpendicular to cartilage-calcified cartilage. Elastic cartilage is found in the external ear,
cartilage interface. the walls of the external auditory canal, the Eustachian
Between 60 and 80 percent of the net weight of tube, the epiglottis and the larynx. Fibrocartilage has
cartilage is water, and this large component of water characteristics intermediate between those of hyaline
accounts for the resilient nature of cartilage. Water is cartilage and dense connective tissue. Its presence
attracted to the negative charges in the abundant sulfate indicates the need for resistance to compression and shear
and carboxyl groups on the GAGs. This hydration forces. It is found in the intervertebral disks, the symphysis
permits diffusion of water-soluble molecules in the pubis, the articular discs of the sternoclavicular and
ground substance. However the movement of large temperomandibular joints, the menisci of the knee joint
molecules and bacteria is inhibited. Cartilage is poorly and some places where ligaments or tendons attach to
vascularized, and gets most of its nutrients through bones. The amount of cartilage in fibrocartilage is
diffusion. In the adult, repair is poor. variable, it generally occupies a smaller amount of the
There are three kinds of cartilage, hyaline cartilage, tissue and there is no perichondrium.
elastic cartilage and fibrocartilage. Hyaline cartilage is the Perichondrium has 2 layers:
most abundant type of cartilage. Most of the skeleton • External—fibrous; made of dense irregular connective
of the fetus is laid down in cartilage before being replaced tissue.
by bone. Hyaline cartilage in the adult is found in the • Internal—cellular (chondrogenic); contains many
nose, parts of the respiratory tract, at the ends of ribs osteoblasts and blood vessels.
and at the articular surfaces of bones. Fine collagenous
fibers are scattered throughout the ground substance, Functions: cartilage nutrition, appositional growth, and
but they are not ordinarily visible in H and E preparations. regeneration.
Thus, the interceIlular substance (matrix) appears
Cells
relatively homogeneous. The cartilage cells are called
chondrocytes and lie within little spaces, the lacunae. • Chondroblasts—less differentiated cartilage cells,
Cells lying within the lacunae are found only in cartilage originate from non-differentiated mesenchyme; have
and bone. Hyaline cartilage, with the exception of that a flattened shape; a well-developed rough
associated with joints (articular cartilage), is surrounded endoplasmic reticulum in a basophilic cytoplasm;
by a dense connective tissue capsule, the perichondrium. function—elaboration of cartilage intercellular matter;
The structure of elastic cartilage is very similar to that under certain circumstances chondroblasts are
of hyaline cartilage, but in addition to the other capable of producing matrix-degrading enzymes -
components, its matrix has elastic fibres and collagenase, elastase, hyaluronidase; reside in the
 Biology of Bone and Cartilage 19

internal layer of periosteum and in the depth of

matrix—within lacunae; chondroblasts mature into
chondrocytes.
• Chondrocytes—differentiated cartilage cells; of round
or angular shapes, with advancing cellular age
chondrocytes progressively lose their rough
endoplasmic reticulum; function—elaboration of
cartilage intercellular matter; under certain
circumstances chondroblasts are capable of
producing matrix-degrading enzymes—collagenase,
elastase, hyaluronidase; reside in the depth of
matrix—within minute special cavities, lacunaes;
sometimes the number of cartilage cells in one lacunae
is more than one, it is the consequence of cell
division; quite often the division is accomplished
Fig. 1.15: Schematic diagram for fluid film lubrication
through amitosis; such cellular groups are called
isogenic groups.

Lubrication Mechanism of Cartilages

There are two types of lubrication mechanisms involved
namely, the boundary lubrication and the fluid film
lubrication. The boundary lubrication depends upon the
chemical adsorption of a monolayer of lubricant
molecules onto the articular surfaces and also depends
on the chemical property of lubricants.
Fluid film lubrication (Fig. 1.15): In this type, a much
thicker film of lubricant causes a relatively large
separation of the two bearing surfaces. Elastohydro-
dynamic fluid films of both the sliding and the squeeze
type probably play an important role in lubricating the
joint. With high load and low speeds of relative motion,
the fluid film will decrease in thickness as the fluid is
squeezed out from between the surfaces. Under very Fig. 1.16: Blood supply of epiphysis
high loading conditions, the fluid film may be eliminated,
allowing surface-to-surface contact.
mainly by the nutrient artery, with the periphery having
Cartilage Replacement Mechanisms an additional supply from metaphyseal vessels . Terminal
branches of these arteries end in capillary loops below
Growth Plate
intact cartilage septae that delineate the end of the
The epiphyseal growth plate is made up of three types cartilage zone. These capillaries drain into the large central
of tissues: the cartilage component divided into distinct vein of the diaphysis. Since there are no branches from
zones, the bony tissue of the metaphysis and the fibrous metaphyseal or epiphyseal arteries to the hypertrophic
tissue that surrounds the growth plate. The vascular zone, this region of the growth plate is avascular. Only
supply to the growth plate is illustrated in Figure 1.16. the proliferative zone has an abundant blood supply.
The secondary ossification centre is supplied by the The cartilage matrix is primarily composed of collagen
epiphyseal artery, branches of which end in the and proteoglycans. These macromolecules play a critical
proliferating cartilage zone. The metaphysis is supplied role in the development and maintenance of a variety
 20 Textbook of Craniofacial Growth

of functions including tissue strength, architecture, and The other main structural component of cartilage is
cell to cell interactions. If abnormal molecules are present proteoglycan. Proteoglycans are proteins with one or
in the matrix, it can lose its functional integrity, lose the more attached glycosaminoglycan side chains, e.g.
organized arrangement of chondrocytes and their closely chondroitin sulphate, heparan sulphate, dermatan
regulated proliferation and biosynthesis will also be sulphate. These sulphated side chains occupy
disrupted. Such abnormalities are called dyschondro- approximately two thirds of the C terminus region of
plasias, and affected individuals suffer from dwarfism. the molecule, while the other third, the carbohydrate-
Fortunately, the understanding of cartilage matrix rich portion, binds to hyaluronic acid. The main
molecules has progressed significantly in recent years with proteoglycan of cartilage is aggrecan, a large proteoglycan
the development of techniques enabling improved composed of approximately 90 percent chondroitin
protein characterization and localization, together with sulphate chains. Aggrecan is found as multi-molecular
the knowledge of the gene structure of many matrix aggregates composed of many proteoglycan monomers
molecules. It is now known that genetic defects of a single (up to 100) bound to hyaluronan. A small link protein
matrix molecule are the cause of some of these helps to stabilize the aggregate. Synthesis of aggrecan
dyschondroplasias. is another specific marker of the chondrocyte phenotype.
Type II collagen is the most abundant of the collagens Another important matrix component is the enzyme
in the growth plate, and since it is found almost exclusively alkaline phosphatase (ALP). ALP is abundant in matrix
in cartilage, it is a specific phenotype marker for vesicles and on the plasma membrane of the maturing
chondrocytes. Type II collagen is composed of three chondrocytes, and is required in the calcification process
identical chains that are wound into the characteristic although the precise mechanism of action remains
triple helix of the collagen molecule. Type II collagen unclear. Growth plate chondrocytes are organized into
molecules form banded fibres seen with the electron different zones (Fig. 1.17) with each cell population being
microscope and are therefore classified as fibre forming part of a different stage of maturation in the
(class I) collagen. In the developing limb and in models endochondral sequence. Zone I has otherwise been
of endochondral ossification, type II collagen synthesis described as the reserve or resting zone. Cells exist singly
can be correlated with chondrogenesis. Type II or in pairs separated by an abundant extracellular matrix,
procollagen may be expressed in two forms, IIA or IIB, and have low rates of proliferation. Proteoglycan synthesis
due to differential splicing of recently transcribed mRNA. and type IIB collagen synthesis is low. However, these
In embryonic human vertebral column, type IIB mRNA cells have a high lipid body and vacuole content that
expression is correlated with cartilage matrix synthesis, has led to the suggestion that this zone is involved with
whereas IIA is expressed in pre-chondrocytes, the cells storage for later nutritional requirements. The adoption
surrounding the cartilage. Type XI collagen, also a class of the term ‘reserve zone’ to describe this region may
I collagen, is present in cartilage matrix and is integrated be inappropriate because these cells do not transcribe
into the interior of type II collagen fibrils. Its function type IIA collagen, the marker of pre-chondrocytic cells,
is not known. Type IX collagen is also found in cartilage, evidence that the cells have already differentiated into
but is not a fibre forming collagen since it will not form chondrocytes, i.e. this is not a germinal layer of ‘mother
supramolecular aggregates alone. Type IX is associated cartilage cells’.
with the exterior of the type II collagen molecules and Zone II is otherwise described as the upper
since it has a single glycosaminoglycan side chain, it is proliferative or columnar region. The function of the
also a proteoglycan. proliferative zones is matrix production and cell division
Type X collagen is a short chain, non-fibril forming that result in longitudinal growth. Chondrocytes assume
collagen with a restricted tissue distribution within the a flattened appearance and are arranged in longitudinal
hypertrophic calcifying region of growth plates in fetal columns. The zone is the true germinal layer of the
and developing bone, where it makes up 45 percent growth plate, with cells actively dividing. Type II collagen
of total collagen. It has been proposed that type X synthesis and mRNA expression increase in this zone,
collagen may play a role in regulating mineralization of as does that of type XI and aggrecan, although in bovine
cartilage calcification, however, this remains to be proven. growth plate type IIB collagen levels are relatively higher.
 Biology of Bone and Cartilage 21

traditional view was that these cells were metabolically

very inactive, and that increasing vacuolation indicated
death by hypoxia. However, these cells are clearly actively
involved in the synthesis of type X and type II collagen.
Improvements in techniques of growth plate fixation that
retain chondrocyte morphology have led to the proposal
that a terminal chondrocyte spends most of its life as
a fully viable cell indistinguishable from hypertrophic
chondrocytes positioned further proximally in the growth
plate. The cells then die by apoptosis, a distinct biological
form of cell death, lasting approximately 18 percent of
a terminal chondrocyte’s lifespan. Apoptosis may be
triggered by the metaphyseal vasculature beyond the
last intact cartilage septum.
Zone VI is the junction of the growth plate with the
metaphysis, the region where the transition from cartilage
to bone occurs. Chondrocyte lysis is evident from empty
lacunae invaded by vascular endothelial loops. The
vascular region of calcified cartilage is the primary
spongiosum, upon which osteoblasts lay down
Fig. 1.17: Schematic diagram of a longitudinal section through unmineralized bone, the osteoid. Metaphyseal bone
the epiphyseal growth plate. B = bone, OB = osteoblast, CC formation is associated with type I procollagen mRNA
= calcified cartilage, C = cartilage matrix expression in the empty lacunae, osteoid, bone and
perichondrium. Type I collagen, a marker of the
Cells of zone III, the lower, more mature region of osteoblast phenotype, is immunolocalized to the same
the proliferating zone, are morphologically no different areas, while types II and X collagen have restricted
from those of zone II, but have decreased DNA synthesis. immunolocalization to calcified cartilage trabecular
Type II collagen synthesis remains high; studies of human remnants within spongy bone. Newly formed woven
fetal growth plate report the highest levels of mRNA for metaphyseal bone is gradually replaced by lamellar bone
type II collagen in these cells (Sandberg et al, 1988). following osteoclastic degradation of bony matrix and
Zone IV is the upper hypertrophic zone, where cell chondroclastic removal of remaining cartilage trabeculae.
size abruptly increases and the columnar arrangement At the same time, external reshaping of the bone is
is less regular. Although not proliferating, hypertrophic brought about by surface osteoclastic bone resorption
zone cells retain the full complement of cytoplasmic and appositional bone formation by periosteally derived
components, and light microscopy reveals increasing osteoblasts.
vacuolation of the cells. Hypertrophic chondrocytes are
Synchondrosis
metabolically active cells, with overall matrix synthesis
per cell increased approximately three-fold, compared The structure in the cranial base which resembles the
to the proliferative zone. The main matrix components growth plates are synchondroses. A synchondrosis is a
synthesized are types II and X collagen and aggrecan. type of immovable joint in which the articulating
Zone V is the zone of the terminal chondrocyte. The structures are joined together by hyaline cartilage.
end of this zone is marked by the last intact transverse Synchondroses are formed between the epiphyses (ends)
cartilage septum. Matrix calcification occurs in longitudinal and diaphyses (shafts) of long bones (Fig. 1.18). It
septae between the columns of chondrocytes, and this includes the numerous temporary cartilaginous junctions
calcified matrix becomes the scaffolding for bone between diaphysis and epiphysis in the immature post
deposition in the metaphysis. The hypertrophic zone cranial skeleton and also in the regions of unossified
contains the highest levels of alkaline phosphatase. The cartilage between skull components developing in the
 22 Textbook of Craniofacial Growth

Fig. 1.19: Bidirectional interstitial growth of synchondrosis

Fig. 1.18: Diagrammatic representation of synchondrosis

chondrocranium (e.g. between the sphenoid and

occipital bones). The most important synchondrosis in
the growth of craniofacial region is spheno-occipital
synchondrosis. The sphenoid bone consists of a central
body and lateral greater and lesser wings. The body is
divided embryologically into a presphenoid segment and
the post sphenoid segments. The presephenoid segment
lies anterior to tuberculum sellae and post sphenoid
segment comprises the sella turcica and dorsum sellae.
These two parts fuse by eight months of fetal life. Posterior
to the post sphenoid, the cartilage of the basilar part
of the occipital bone becomes ossified simultaneously.
Both the postsphenoid and basilar occipitalis continue Fig. 1.20: Cross-section of nasal cartilage
ossification until all that remains is a plate of cartilage
between them, called the spheno-occipital synchondrosis.
Growth of spheno-occipital synchondrosis is responsible bone. Histological examinations reveal that there is
for lengthening between foramen magnum and sella endochondral ossification taking place at the septo-
turcica. This continues up to latter half of second decade ethmoidal junction and that there is an area of
of life. The cellular arrangement of synchondroses proliferation at the vomeral edge of the cartilage. In the
suggests that it looks like butting together of two growth palatal area, there is resorption on the nasal side and
plates with reserve cartilage layers back to back. As a apposition on the oral side of the bony palate. These
result of this arrangement, interstitial expansion is findings appear to support the general opinion. The role
bidirectional, increasing the size of the bones in both of the cartilaginous nasal septum has been discussed by
sides simultaneously (Fig. 1.19). many authors also and the general consensus seems to
be that it provides a thrusting force which carries the
Nasal Cartilage (Fig. 1.20)
maxilla forward and downward during growth.
Nasal cartilage is a thin cartilaginous plate located between In prenatal life, nasal septum cartilage lies behind
vomer, perpendicular plate of the ethmoid and nasal the cranial base cartilages. In front and below it is
 Biology of Bone and Cartilage 23

attached to premaxillary bone. The lower edge is attached in the long bones, seems to be absent in the condyle.
to vomer. Posteriorly it merges with mesethmoid In regard to the function of the condylar cartilage,
cartilage. differences have been found to exist between it and the
epiphysis. The condylar cartilage is highly responsive to
Condylar Cartilage mechanical stimuli and responds differently from the
The condylar cartilage is a secondary type of cartilage epiphyseal cartilages to various hormonal and chemical
which was transformed phylogenetically from the agents. The decisive point is the question of the tissue-
periosteum. Secondary (accessory or embryonic) separating force or the independent growth-promoting
cartilages are local mesenchymal cartilage formations, potential. As mentioned earlier, the existence of this force
primarily associated with membrane bones or with or potential has been implicit in the interpretation of the
fracture of long bones; ontogenetically and phylogeneti- function of the condylar cartilage in most descriptions
cally they do not develop from the primary cartilaginous of the condyle. This problem can again be tackled by
skeleton. Apart from the embryonic origin, the condylar way of transplantation. If the condylar cartilage is
cartilage differs from primary cartilages (such as the transplanted to a relatively nonfunctional site, such as
epiphyseal growth plates and the synchondroses) in the subcutaneous or brain tissue, it does not maintain
growth pattern, in histologic organization, and in its structure and does not behave like the condylar
antigenicity. cartilage in situ. Only when it is accompanied by a piece
This cartilage is a latecomer, a secondary cartilage, of adjacent bony ramus may the transplant grow, and
and not a part of the Meckel's cartilage that acts as the even then the structure is not maintained in the beautiful
model for the early development of the mandible. It manner as observed in transplanted epiphyseal cartilages.
is not an articular cartilage, nor is it an epiphyseal growth Tissue-culture studies have also demonstrated lack of
plate. It does not even form from the same embryonic growth of the condylar cartilage.
precursor tissue as the epiphyseal cartilages, a fact which There are four different zones in the condylar
may have something to do with its structure and function. cartilage. The outer dense fibrous connective tissue zone
It is claimed that the condylar cartilage grows not that are sparsely vascular. Then the proliferation zone
interstitially, like the epiphyseal car tilages, but of undifferentiated connective tissue cells which becomes
appositionally from the deepest layer of the connective differentiated to chondroblasts. The hyaline cartilage
tissue cover of the condyle. This mitotic layer responsible zone with randomly distributed chondroblasts and
for the increase of the cartilage is also called the hypertrophied cells. The matrix of these cells is more
intermediate layer. It is located between the surface of towards the condyle (Fig. 1.21).
the condyle and the cartilaginous portion of it, and the The endochondral ossification zone in which the
cells of this layer are not cartilage cells but are rather cartilage is resorbed and replaced with trabecular bone.
like undifferentiated mesenchymal cells. In the epiphyseal Condylar cartilage can be differentiated from the
cartilages, as we know, the proliferating cells are cartilage epiphyseal cartilage in that the outer fibrous covering
cells. There are other differences between the condylar is only present in condylar cartilage. In the epiphyseal
cartilage and the epiphyseal growth cartilages. The cartilage mineralization starts only below the
structural organization present in the epiphyseal growth hypertrophied layer, whereas in condylar cartilage the
apparatuses is lacking in the condylar cartilage, and the mineralization starts in the hypertrophied layer. The
zone of nonhypertrophic cartilage cells in the condyle condylar cartilage does not have a matrix surrounding
is very narrow, the forming cartilage cells turning its cells in contrast to the epiphyseal cartilage.
hypertrophic almost immediately, as in the clavicle. It
Primary and Secondary Cartilages
is of special interest that the whole hypertrophic area
in the condylar cartilage seems to be in a state of The features of primary cartilages are:
mineralization, whereas in the epiphyseal growth • They are derivatives of primordial cartilage.
apparatuses only the degenerative zone is mineralizing. • In primary cartilage, chondroblasts divide and
Finally, the so-called primary spongiosa, always present synthesize intercellular matrix.
 24 Textbook of Craniofacial Growth

4. Deng ZL, Sharff KA, Tang N, et al. Regulation of osteogenic

differentiation during skeletal development. Front Biosci
2008;13:2001-21.
5. Goose Denys H, Appleton John. Human Dentofacial
growth; Pergamon Press, Oxford, England, 1982.
6. Henriksen K, Leeming DJ, Byrjalsen I, et al. Osteoclasts
prefer aged bone. Osteoporos Int 2007;18(6):751-9.
7. Junqueira LC, Carneiro J, Long JA. Bone. Basic Histology.
5th edn. Norwalk, Conn: Appleton-Century-Crofts;
1986;140-65.
8. Karsdal MA, Martin TJ, Bollerslev J, Christiansen C,
Henriksen K. Are nonresorbing osteoclasts sources of bone
anabolic activity? J Bone Miner Res 2007;22(4):487-94.
9. Kollet O, Dar A, Lapidot T. The multiple roles of osteoclasts
in host defense: bone remodeling and hematopoietic stem
cell mobilization. Annu Rev Immunol 2007;25:51-69.
10. Leblond CP. Synthesis and secretion of collagen by cells
of connective tissue, bone, and dentin. Anat Rec 1989;
224(2):123-38.
11. Li X, Qin L, Bergenstock M, et al. Parathyroid hormone
stimulates osteoblastic expression of MCP-1 to recruit and
Fig. 1.21: Structure of condyle
increase the fusion of pre/osteoclasts. J Biol Chem
2007;282(45):33098-106.
12. Marks SC Jr, Popoff SN. Bone cell biology: the regulation
• The dividing chondroblasts are surrounded by of development, structure, and function in the skeleton. Am
cartilaginous matrix. J Anat 1988;183(1):1-44.
13. McCarthy EF, Frassica FJ. Anatomy and physiology of bone.
• Cells arranged in columnar fashion Pathology of Bone and Joint Disorders. Philadelphia, Pa:
• Since surrounded by cartilaginous matrix, primary WB Saunders 1998;25-50.
cartilage is not influenced by local environmental 14. McHugh KP, Shen Z, Crotti TN, et al. Role of cell-matrix
factors, e.g. Epiphyseal cartilages, synchondroses interactions in osteoclast differentiation. Adv Exp Med Biol
• Growth is interstitial. Hence 3 dimensional growth 2007;602:107-11.
15. Miller EJ, Gay S. The collagens: an overview and update.
• Considered to be a genetic pacemaker for growth.
Methods Enzymol 1987;144:3-41.
Features of secondary cartilages include: 16. Moore KL. Clinically Oriented Anatomy, 3rd edn.
• Secondary cartilage forms on a membranous bone Philadelphia, Williams and Wilkins 1992;11-19.
• No intercellular matrix 17. Mundy GR. Bone resorption and turnover in health and
• Not surrounded by cartilaginous matrix disease. Bone 1987;8 (suppl 1):S9-16.
• Cells are arranged in haphazard manner 18. Nijweide PJ, Burger EH, Feyen JH. Cells of bone:
proliferation, differentiation, and hormonal regulation.
• Affected by external influences which will stimulate Physiol Rev 1986;66(4):855-86.
growth of cartilage, e.g. condylar cartilage 19. Owen M. Histogenesis of bone cells. Calcif Tissue Res
• Only peripheral growth takes place 1978;25(3):205-7.
• Contributes only to regional adaptive growth. 20. Porter GA, Gurley AM, Roty SI. Bone. In: Sternberg SS, ed.
Histology for Pathologists, 2nd edn. New York, NY: Raven
BIBLIOGRAPHY Press 1997;85-106.
21. Ranly Don. A synopsis of Craniofacial growth, 2nd edn,
1. Adler CP. Bones and bone tissue: Normal anatomy and Appleton and Lange, 1980.
histology. Bone Diseases. New York, NY: Springer-Verlag; 22. Robinson RA. Bone tissue: composition and function. John
2000;1-30. Hopkins Med J 1979;145:10.
2. Athanasou NA. Cellular biology of bone-resorbing cells. J 23. Thommesen L, Stunes AK, Monjo M, et al. Expression and
Bone Joint Surg Am 1996;78(7):1096-112. regulation of resistin in osteoblasts and osteoclasts indicate
3. Boskey AL. Noncollagenous matrix proteins and their role a role in bone metabolism. J Cell Biochem 2006;99(3):
in mineralization. Bone Miner 1989;6(2):111-23. 824-34.
 2 Physiology of Bone

CHAPTER OUTLINE can adapt to mechanical, metabolic, and hormonal

• Bone Turnover stimuli or stresses. For many years, researchers have tried
• Modeling and Remodeling to understand the mechanical influences on living bone.
• Basic Multicellular Unit (BMU)
• Mechanical Influence on Bone MODELING AND REMODELING (FIG. 2.1)
• Bone Regulators
• Purpose of Bone Remodeling The physiologic concept of bone remodeling (turnover)
• Goals of Remodeling is largely attributed to important biologic activities like
• Remodeling Process modeling and remodeling. Most experiments and theory
• Reactions of Bone about bone adaptation are concerned with the placing
• Bone Assessment Methodologies
or replacing of bony mass. This is usually termed
‘modeling’ and is produced by the probably rather
Bone is a complex, living tissue that is constantly
adapting to metabolic and structural demands. Because
it is a mineralized tissue, all changes in external osseous
form occur along vascularised periosteal surfaces via
uncoupled anabolic and catabolic modeling events. The
ability of a bone to function effectively under the loads
that are imposed on it depends upon two factors: the
properties of the bone material, and arrangement of
this material in space—the size and shape of the bone.
Eugene Roberts referred orthodontists as craniofacial
bone specialists and hence a thorough knowledge about
bone physiology will help the orthodontist to deal with
the patients more effectively and efficiently.

BONE TURNOVER
Mature bone undergoes a continuous process of
resorption and formation known as remodeling.
Osteoclasts remove old bone by acidification and
proteolytic digestion. Later, osteoblasts migrate to this
Fig. 2.1: Schematic diagram illustrates the integration of
area, and deposit osteoid, into the cavity. The collagen anabolic and catabolic modeling activity (M) along bone
then becomes infused with calcium phosphate mineral. surfaces with internal remodeling (R) (turnover) to produce
Remodeling provides a mechanism whereby the skeleton new secondary osteons
 26 Textbook of Craniofacial Growth

uncoordinated activity of bone cells. It should be

distinguished from 'remodeling' which is also a matter
of lively concern, particularly where it occurs in cancellous
bone, in which osteoclasts and osteoblasts work together
in a coordinated sequence to replace bone and usually
leave the total amount of bone unaltered, in the form
of secondary osteons (Haversian systems).
The modern physiologic concept of bone remodeling
(turnover) is largely attributed to Frost. Harold Frost,
(1922-2004) is considered to be the father of the modern
concepts of bone physiology for his extensive work. Frost Fig. 2.2: A schematic illustration, of a longitudinal section
through a cutting/filling cone in cortical bone, illustrates the
differentiates bone "modeling" from “remodeling”. Bone perivascular cellular activity associated with the coupled
modeling is a mechanically mediated adaptive process resorption (R) and formation (F) responses
for changing a bone's size, shape, or position. Bone
modeling is an uncoupled process, meaning anabolic
and catabolic sites are controlled independently. Bone
modeling, an important element of skeletal growth, readily demonstrated in cortical bone but there is
functions as a lifelong optimization process for adapting compelling evidence for the same concept in cancellous
bone mass and architecture to functional needs. bone. Parfit (1994) states that a fully developed BMU
Modeling also called as macro modeling by some authors consists of a team of osteoclasts in front forming the cutting
is an activity primarily found during growth and is cone or hemicone, a team of osteoblasts behind forming
responsible for the final shape of the bones. Bone the closing cone or hemicone, some form of blood
Remodeling is the physiologic term for internal turnover supply, and associated connective tissue (Fig. 2.2). The
of a mineralized tissue, without a change in its overall BMU exists and moves in three dimensions, excavating
form. It is a coupled sequence of catabolic (resorptive) and refilling a tunnel through cortical bone or a trench
and anabolic (osteogenic) events to support calcium across the surface of cancellous bone. A cortical BMU
homeostasis and repair (renew) aged or damaged travels for about 4000 μm at about 20 μm/day, taking
mineralized tissue. Both modeling and remodeling are about 200 days. A cancellous BMU travels about half
the result of the controlled activity of osteoblasts and this distance at about half the speed, taking about the
osteoclasts. The difference is in modeling, both these same period of time. While moving through or across
two cells act over a large surface area, removing or the surface of bone, the cellular components of a BMU
forming large volumes of bone mass which is active maintain the same spatial and temporal relationships to
during growth period. Remodeling on the other hand each other.
is active throughout life and serves to modify shape of
skeleton, architecture, bone volume and to repair MECHANICAL INFLUENCE ON BONE
microdamage. It is generally accepted that mechanical load plays an
important role in maintenance and adaptation of the
BASIC MULTICELLULAR UNIT (BMU)
skeleton. Bone mass and bone architecture are believed
Bone replacement either by modeling or remodeling is to be adapted to the external loading conditions. Wolff
initiated by osteoclastic resorption followed soon after in 1892 put forward the famous law of transformation
by osteoblastic formation. These are commonly regarded of bone which states that Every change in the form and
as independent processes, but in reality resorption and function of bone or of their function alone is followed
formation are closely linked within discrete temporary by certain definite changes in their internal architecture
anatomic structures, first described by Frost who gave and equally definite alteration in their external
them the name “basic metabolizing units”, a term he conformation, in accordance with mathematical laws.
later changed to “basic multicellular units”, usually This paved way for many pioneers like Sicher, Frost, to
abbreviated BMU. The individuality of the BMU is most do extensive research in bone physiology.
Other documents randomly have
different content
The text on this page is estimated to be only 24.95%
accurate

hers for the gases. Alternate three or four of with a spacer.

Place the last plugs so that you still have jfifch of empty space
before the end of the tube. You SYill also have about 2 inches or so
of open space at the of this tube (the end that mounts to the
w&apprii That's fine, because that is your first expansion chamber it
needs to be large to handle the initial rush of explosive gases that
follow the bullet out of the barrel. Next, combine the two tubes by
sliding t end of the smaller into the larger. You may make an
electrical-tape bushing on the is snug, depending on how much the
two tubes. The screen end against the final section larger tube.
Check the i as seal, apply some . If you wish , use a or liquid), or
some form of aluminum You need to align the silencer and the bore
after you mount the unit on the weapon. Use the hose clamp; a
setscrew^ a compression fitting to secure tlli unit to the gun. Make it
snug so the silencer is ***** Friends, this is the end of our how-to
section fbr book. As l noted in the last chapter, I welcome )
^^resporidence and ideas on silencer designs . , . purposes only, of
course. I am Gee am available at P.O. ». Thank you. W 7*
The text on this page is estimated to be only 22.40%
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CHAPTER 7 Wfe're The tools f&u'we up" the slight amount

of scraps and minor construction the kitchen table, and you've got a
nice three for your favorite firearms* Again, like a board-certified
Jewish grandmother nagging you to eat sure As you all know, I am a
stii ion, and I want you to be, too* must have had the feds in when
he wrote, "Mankind are very odd creatures, half censure what they
practice, the other half practice what they censure/' Also, only a
hard-core, terminal cynic would think that you do anything illegal.
I'm in this book to help you circumvent or ignore the laws about si I
The text on this page is estimated to be only 17.10%
accurate

72 Therefore, treat this book and Its design plans for

entertainment and educational purposes only until you have satisfied
the local, state, and federal governments and their various clerical
and enforcement minions. After all, they are servants of We, the
People. Or, to paraphrase Edgar Allen Pm, the pnlf thing the mon
people have to do with laws ifto ’obey;fhem., Sb Pfeey ttese great
laws out there, folks, And enjoy your silencers. As I've written, these
designs really work. But do your work carefully and safely. Firearms
and silencers are dangerous to people on either side of the muzzle,
so please use all sorts of good sense and caution. Don- 1 get
careless and don't get hurt. As the gentle and wise preeinct rolhcall
sergeant: on Chilli Street Bluest used::fe say, "Let's be careful out
there/' As a final bit of homily. In every: book I've ever written, I
have always cautioned people against doing anything In anger or
bragging about what you are going to do or have done. This is
especially important when firearms are concerned and even more so
in the case of silencers. Face it; silencers have a bad reputation
despite the feet: that they are simply combination pf metal, .plasiii*.
rubber and other materials engineered, into a sound muffler, ft's the
irresponsible silencer user who deserves the reputation. So be cool.
Keep it very quiet if you're having fun with silencers. And always
remember the words of Henry Wheeler Shaw, a wonderful American
humorist who used the pen name Josh Billings; "Silence is one of the
hardest arguments to refute/'
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