576866

research-article2015
TAB0010.1177/1759720X15576866Therapeutic Advances in Musculoskeletal DiseaseML Tiku and HE Sabaawy

Therapeutic Advances in Musculoskeletal Disease Review

Cartilage regeneration for treatment of

Ther Adv Musculoskel Dis

2015, Vol. 7(3) 76­–87

osteoarthritis: a paradigm for nonsurgical DOI: 10.1177/

1759720X15576866

intervention
© The Author(s), 2015.
Reprints and permissions:
http://www.sagepub.co.uk/
journalsPermissions.nav

Moti L. Tiku and Hatem E. Sabaawy

Abstract: Osteoarthritis (OA) is associated with articular cartilage abnormalities and affects
people of older age: preventative or therapeutic treatment measures for OA and related
articular cartilage disorders remain challenging. In this perspective review, we have integrated
multiple biological, morphological, developmental, stem cell and homeostasis concepts
of articular cartilage to develop a paradigm for cartilage regeneration. OA is conceptually
defined as an injury of cartilage that initiates chondrocyte activation, expression of proteases
and growth factor release from the matrix. This regenerative process results in the local
activation of inflammatory response genes in cartilage without migration of inflammatory cells
or angiogenesis. The end results are catabolic and anabolic responses, and it is the balance
between these two outcomes that controls remodelling of the matrix and regeneration. A
tantalizing clinical clue for cartilage regrowth in OA joints has been observed in surgically
created joint distraction. We hypothesize that cartilage growth in these distracted joints may
have a biological connection with the size of organs and regeneration. Therefore we propose
a novel, practical and nonsurgical intervention to validate the role of distraction in cartilage
regeneration in OA. The approach permits normal wake-up activity while during sleep; the index
knee is subjected to distraction with a pull traction device. Comparison of follow-up magnetic
resonance imaging (MRI) at 3 and 6 months of therapy to those taken before therapy will provide
much-needed objective evidence for the use of this mode of therapy for OA. We suggest that the
paradigm presented here merits investigation for treatment of OA in knee joints.

Keywords: articular cartilage, osteoarthritis, cartilage injury, cartilage repair, cartilage regenera-
tion, cartilage organ size, osteoarthritis treatment, joint distraction, nonsurgical intervention

Introduction or treatment of OA; the only medical option for Correspondence to:
Moti L. Tiku, MD
It is estimated that about 10% of the world’s pop- OA involves pain management. In this context, Department of Medicine,
ulation aged 60 years or older have significant cartilage tissue engineering has not held the high Robert Wood Johnson
Medical School, New
clinical problems that could be attributed to oste- promises of therapy in OA [Huey et al. 2012] and Brunswick, NJ 08903-
oarthritis (OA) [Cooper et al. 2013]. The health- the potential for cartilage regeneration through 2681, USA
[email protected].
care burden of OA on the society is enormous stem cell therapy has not yet fully materialized edu
because this disease progressively affects the age- [Djouad et al. 2009; Johanson et al. 2012]. Hatem E. Sabaawy, MD, PhD
ing population. Moreover, the ever changing pop- Accordingly, total joint replacement, though Rutgers Cancer Institute of
New Jersey, Robert Wood
ulation demographics further increase the cost of expensive, is considered a final option for reliev- Johnson Medical School,
healthcare to society, and add pain and disability ing pain and regaining function in patients with New Brunswick, NJ, USA

to a large segment of the population. Trauma, OA [Gossec et al. 2011].

degenerative joint diseases, metabolic factors
such as obesity and mechanical factors such as Articular cartilage is thought to have limited
joint instability are among the common aetiologi- regeneration potential [Huey et al. 2012].
cal factors of OA [Felson, 2009]. Presently, there However, it has been observed that symptomatic
are no pharmacological agents for the prevention pain relief and cartilage regeneration are possible

76 http://tab.sagepub.com
 ML Tiku and HE Sabaawy

in OA joints that have been surgically pulled apart 1996]. Superficial zone proteins homologous to
or distracted for a prolonged periods of time proteoglycan 4 are encoded by the Prg4 gene,
[Wiegant et al. 2013]. This might have been a clue which provides lubrication and a load-bearing
that cartilage regeneration is possible in OA joints. surface for the articular cartilage [Ikegawa et al.
However, the mechanism(s) by which cartilage 2000]. The middle or transitional zone comprises
growth might occur in the distracted joint space ~40–60% of the cartilage thickness. Chondrocytes
are unknown. In this perspective, we analyse the in this middle zone are surrounded by randomly
biological aspects of cartilage development, organized collagen type II fibrils with high con-
including injury and growth, and present a con- centrations of aggrecan, hyaluronic acid and der-
ceptual context for cartilage regeneration in the matan sulfate (Figure 1). However, chondrocytes
distracted OA joints. Accordingly, we propose a in the deep zone are ellipsoid, and these cells are
novel paradigm for nonsurgical joint distraction stacked in cell columns surrounded by a special-
treatment of OA. ized PCM and interspersed by a radially oriented
collagen matrix [Poole, 2005; Wilusz et al. 2014].
Between the deep zone of cartilage and calcific
Cartilage structure cartilage in adults is a specialized amorphous
Articular cartilage is a unique tissue between the material resembling a basement membrane called
ends of bones in the joints that helps in load bear- the tidemark (Figure 1).
ing and lubrication. It is rich in extracellular
matrix with scattered chondrocytes [Poole, 2005].
Adult cartilage has zonal architecture consisting Cartilage development
of superficial, middle, and deep zones [Grogan Development of articular cartilage and synovial
et al. 2013]. These zones vary in matrix biochemi- joint structures is tightly synchronized [Koyama
cal composition, cell density and morphology, cell et al. 2008; Sandell, 2012; Iwamoto et al. 2013].
metabolism and the pericellular matrix (PCM) Initially at the prospective joint sites, expression
[Wilusz et al. 2014]. The superficial zone extends of Sox9/Col2/doublecortin (DCX) in anlagen
~10–20% of the full thickness of the articular car- occurs in response to undefined upstream mor-
tilage. Chondrocytes in this zone are elongated, phogenetic and determination mechanisms, and
flattened, oriented parallel to the cartilage surface results in the expression of Gdf5 in the interzone
and are surrounded by densely packed collagen mesenchymal population [Decker et al. 2014].
fibrils with low levels of aggrecan but higher con- This specific population of Gdf5-expressing
centrations of decorin and biglycan [Poole et al. joint progenitor interzone cells maintain DCX

Figure 1. Hypothetical models of development of articular cartilage. Left panel shows growth through
apposition. Middle panel suggests growth from bottom of cartilage attached to the bone towards cartilage
surface in the joint cavity. Right hand panel suggests cartilage growth could be random from bottom and top of
the cartilage.
Left side of figure is modified from Hayes et al. [2001]
TA, transit-amplifying; TD, terminal differentiation.

http://tab.sagepub.com 77
Therapeutic Advances in Musculoskeletal Disease 7(3)

expression [Zhang et al. 2011]. In developing with growth plate chondrocytes, is also required
(digits) joints, Tgfbr2 positive cells reach the for interzone cells and joint formation [Longobardi
interzone sites in spatiotemporal distribution [Li et al. 2012].
et al. 2013]. First, Tgfbr2 positive cells are limited
to the dorsal and ventral regions but undetected Developing joints next undergo cavitation to cre-
in the central region of the interzone [Spagnoli ate the synovial cavity that is filled with lubricants
et al. 2007; Li et al. 2013]. Later on, anlagen- containing the synovial fluid. It has been known
bound chondrocytes turn on the expression of for a long time that immobilization by experimen-
matrillin-1. Gdf5 cells that subsequently express tal nerve damage inhibits cavity formation in the
Sox9/Col2, and are positive for the expression of developing joints [Fell and Canti, 1934]. Joint
matrillin-1, differentiate into all other chondro- movement stimulates the establishment of joint
cytes, while cells negative for mitrillin-1 expres- superficial cell phenotype and the production of
sion evolve into articular chondrocytes [Hyde essential lubricants such as hyaluronate and
et al. 2007]. This process involves specific action lubricin [Dowthwaite et al. 2003]. Recent studies
of regulatory genes including Erg and PTHrP using muscleless mouse embryo mutants have
[Iwamoto et al. 2007; Chen et al. 2008; Li et al. revealed that joint progenitor cell fate is not main-
2013]. Postnatally, Gdf5 and Tgfbr2-positive and tained in these embryos; neither Wnt/β-catenin
-negative interzone cells and their progeny give signalling is activated nor the joints have formed
rise to multiple joint tissues including articular properly [Pazin et al. 2012]. Further studies
cartilage, intrajoint ligaments, synovial lining cells revealed that there might be differential require-
and other joint-specific structures such as the ments for muscle-derived movements at joints
meniscus in the knee [Decker et al. 2014]. such as the elbow joint compared with a more
Moreover, Tgfbr2 expressing cells constitute the essential requirement for Tgfbr2 signalling for
slow cycling stem/progenitor cell population that knee joint formation [Pazin et al. 2012].
are distributed with specific cell niches of joint Nevertheless, data from ongoing research studies
such as in the groove of Ranvier [Li and Xie, 2005; that are examining joint development indicate
Li et al. 2013]. that, developmentally, articular chondrocytes are
different from growth plate hypertrophic chon-
Observations made through examining cartilage drocytes [Iwamoto et al. 2013]. Perhaps these
development in mice that are mutant for Noggin, studies may provide a key towards our under-
Wnt4/Wnt9a, Tgfbr2 or β-catenin revealed the standing of cartilage regeneration and finding
presence of joint ablations and cartilage fusions. clues for treatment of cartilage injury.
Similarly, mouse embryos deficient in the Tgfβ-
activated kinase 1, heparin sulfate synthase Ext1
or Indian hedgehog (Ihh) also demonstrated joint Cartilage stem cells
defects [Gunnell et al. 2010; Mundy et al. 2011]. After skeletal maturity, articular chondrocytes
Furthermore, mouse embryo mutants for the stop proliferating and are slow to replace. These
master chondrogenic genes, Sox5 and Sox6, also cellular characteristics are also exhibited by stem
display defects of limb skeletogenesis and joint cells [Blanpain et al. 2007]. When cultured, iso-
development [Dy et al. 2010]. Similarly, the lated articular chondrocytes form cobblestone
absence of the zinc finger transcription factors sheets of overlapping cells and cartilage-like tis-
Osr1 and Osr2 limits the sustained expression of sue. Chondrocytes exhibit characteristics of trans-
Gdf5, Wnt4 and Wnt9a in interzone cells leading formed cells, such as anchorage-independent
to fusion of limb joints [Gao et al. 2011]. Also, growth, preference of a rounded cell shape and
ablation of C-Jun, which is an upstream regulator growth in nude mice [Benya and Shaffer, 1982;
of Wnt9a, results in deranged Wnt signalling and Dell’accio, 2001]. These cell characteristics have
lack of progression of joint formation [Kan and been mostly associated with the cell biology of
Tabin, 2013]. Collectively, these molecular regu- chondrocytes and need further reconsideration in
lators act at both local and distant levels and par- the context of the features of cartilage stem cells.
ticipate in the regulation of gene expression in
interzone cells, and therefore control their cell Several independent research groups have dem-
fate and function. Adding to the ever expanding onstrated that cells isolated from the superficial
list of factors regulating cartilage development zone of adult articular cartilage from various
that were delineated above, low expression of sources including human tissues have progenitor
chemokines and in particular MCP-5, compared cell characteristics such as high colony formation

78 http://tab.sagepub.com
 ML Tiku and HE Sabaawy

and expression of mesenchymal stem cell markers niche in the joint that could have significant roles
[Dowthwaite et al. 2004; Hattori et al. 2007]. in repair and regeneration [Li et al. 2013].
Furthermore, after multiple passages, these cells However, given these observations, the progenitor
express a chondrogenic phenotype and, in cells in perichondrial groove of Ranvier will have
response to Tgfb, cells respond with enhanced an anatomical and physical barrier to traverse to
synthesis of lubricin and cartilage specific matrix the site of injury in the cartilage that usually
components [Dowthwaite et al. 2004; Hattori occurs where the joint is subjected to repeated
et al. 2007]. Furthermore, Tgfb and Wnt/β- traumas – away from groove of Ranvier. However,
catenin signalling regulate proliferation and dif- it is still possible that progenitor cells of groove of
ferentiation of these cells [Dowthwaite et al. 2004; Ranvier could be involved in increasing the cir-
Hattori et al. 2007]. cumference of the developing adult articular
cartilage.
Immunohistochemistry of normal cartilage sec-
tions shows large numbers of chondrocytes with Bone marrow is rich source of hematopoietic and
staining for stem cell markers such as Notch-1, mesenchymal stem cells [Li and Xie, 2005].
Stro-1 and VCAM-I throughout various zones Based on this concept, procedures for marrow
[Grogan et al. 2009]. Stem cell surface markers stimulation including transcortical Pridie drilling,
such as CD44, CD151, CD105 and CD166 have abrasion arthroplasty and microfracture rely on
also been demonstrated in chondrocytes mesenchymal stem cells and growth factors com-
[Alsalameh et al. 2004]. Interestingly, Hoechst ing from the bone marrow and have been advo-
33342 dye exclusion, a feature of stem cell side cated for cartilage regeneration [Schindler, 2011].
population, is equally distributed in normal and Koelling and colleagues observed that chondro-
OA chondrocytes [Grogan et al. 2009]. genic progenitor cells migrate to the damaged
Furthermore, normal and osteoarthritic articular articular cartilage from the bone marrow through
cartilage contains high number of CD105 and the subchondral bone [Koelling et al. 2009].
CD166 cells. In particular, the cell population
containing CD166-positive cells have strong Collectively, it is unclear if there is a special niche
chondrogenic potential and were exclusively within the confines of the articular cartilage
located in the superficial and middle zone [Pretzel that might support stem cell regeneration.
et al. 2011]. Differentiated chondrocytes showing stem cell
markers indicate the transit-amplifying nature of
Studies have also demonstrated that the synovium these cells but their significance in cartilage regen-
and infrapatellar fat pad contain mesenchymal eration is still unclear [Blanpain et al. 2007;
stem cells, and it has been suggested that these Doupe et al. 2012; Tata et al. 2013].
progenitor cells could be utilized for cell-based
tissue engineering and treatment of cartilage
regeneration [De Bari et al. 2001; Dragoo et al. Cartilage maintenance
2003; Futami et al. 2012]. Mesenchymal stem Homeostasis of the articular cartilage is main-
cells have also been found in the synovial fluid of tained by the right balance between aggrecan and
normal knee joints and their number increases in collagen contents to provide a physiochemical
synovial fluid of diseased joints [Jones et al. 2008; structure for compressive and tensile strength for
Morito et al. 2008]. Karlsson and colleagues stud- joint load and mobility [Poole, 2005]. Aggrecan
ied BrdU labelling of adult rabbit knee joints and molecules are noncovalently associated with col-
showed that cell labelling in the perichondrial lagen fibrils and minor conditions such as immo-
groove of Ranvier is indicative for progenitor cells bility can cause its loss from the cartilage [Vertel,
[Karlsson et al. 2009]. Moreover, these progeni- 1995]. However, chondrocytes rapidly replenish
tor cells also stained for stem cell markers includ- aggrecan. On the other hand, human collagen
ing Stro-1, Jagged1 and BMPr1a [Karlsson et al. type II in cartilage matrix is a long-lived protein,
2009]. As described above, Tgfbr2 expressing with an estimated halflife of >117 years [Verzijl
cells contribute to joint development and popula- et al. 2000]. Thus, its breakdown, synthesis and
tions of these slow cycling stem/progenitor cells maturation are complex and prolonged processes,
are present in the perichondrial groove of Ranvier, and may be key limiting factors for regeneration
synovium, articular cartilage superficial layer and of cartilage. Attrition of superficial chondrocytes
tendon sites of joints. These authors suggested by mechanical forces in the joint is likely replaced
that this might be a specific site for a stem cell through its progenitor activity in a homeostatic

http://tab.sagepub.com 79
Therapeutic Advances in Musculoskeletal Disease 7(3)

process. However, the middle and deep zones of cartilage. The inflammatory gene responses that
cartilage show slow turnover of cells or matrix. follow injured cartilage are not simply the same as
those induced by agents such as interleukin 1α
(IL-1α), and they are also independent of the
Cartilage injury and mechanisms of repair effects of either gene activation or products from
Ideally, a cartilage injury should heal without a noncartilaginous tissues of the joints. In the
scar formation. Scar tissues within the joint would injured cartilage, there is activation of the three
interfere with the smooth surface and would have MAP kinases JNK, p38 and extracellular-signal-
deleterious mechanical properties. However, regulated kinase (ERK), as well as Src kinases,
embryonic skin wounds heal without scar forma- phosphatidylinositol 3-kinase (PI3K) and NF-kB
tion and are achieved by rapid re-epithelialization [Chong et al. 2013; Watt et al. 2013]. In addition,
of wounds with little involvement from basal epi- hosts of other genes are also activated in injured
dermal cells [Degen and Gourdie, 2012]. cartilage, including those coding for cytokines
Embryonic wound edges are pulled together in a and chemokines such as IL-1α, IL-6 and CCL2
purse-string manner and small wounds in the gut [Burleigh et al. 2012].
epithelium also heal in this fashion [Degen and
Gourdie, 2012; Polk and Frey, 2012]. In an in vitro The injury response in cartilage can be categorized
wound model of bovine and human cartilage, it into catabolic and anabolic. Catabolic activity that
was observed that superficial zone chondrocytes is most pertinent to cartilage is the release of the
rapidly proliferated, migrated and spread over the aggrecan-degrading enzyme disintegrin, metallo-
injured cartilage surface in a manner resembling proteinase with thrombospondin motifs 5
re-epithelialization of wounds [Seol et al. 2012]. A (ADAMTS-5) and the collagenase matrix metallo-
cartilage injury does not involve fibrin clot forma- proteinase 13 (MMP-13), which specifically
tion, recruitment of inflammatory cells or angio- degrade type II collagen. ADAMTS-5 is released
genesis [Martin, 1997]. However, cartilage tissue early in response to injury and MMP-13 expression
actively resists vascularization by producing anti- shows a delayed response [Burleigh et al. 2012]. In
angiogenic components such as thrombospon- contrast, the anabolic activity includes the induc-
din-1, chondromodulin-1, SPARC (secreted tion of chondroprotective genes such as tumor
protein acidic and rich in cysteine), collagen type necrosis factor-inducible gene 6 protein (TSG-6),
II derived N-terminal propeptide (PIIBNP), and hyaluronan-binding anti-inflammatory molecule,
the type XVIII derived endostatin [Patra and tissue inhibitor of metalloproteinases-1 (TIMP-1)
Sandell, 2012]. Furthermore, calcific cartilage and activin A – a transforming growth factor beta
and tidemarks are two anatomical barriers for the (TGF-β) family member [Burleigh et al. 2012].
vascularization of articular cartilage. In OA, there
are multiple depositions of tidemarks, as if to ward Several mechanisms control the signalling of
off vascularization from the subchondral bone. In inflammatory gene responses in a cartilage injury.
support of this notion, injection of vascular growth Cartilage is a mechanosensitive tissue and pertur-
factors in the joint cavity induces OA demonstrat- bation of the matrix could signal the activation of
ing its adverse effect in the joint [Ludin et al. chondrocyte surface receptors, such as that of
2013]. integrins, calcium ion channels, primary cilium
and discoidin domain receptors [Leong et al.
Murine and other animal models of OA usually 2011; Burleigh et al. 2012; Vincent, 2013]. When
involve cutting the medial meniscotibial ligament the integrity of the PCM is breached and sub-
of knee joints. Microarray analysis of genes jected to cyclic compression, this results in the
expressed in whole joints or microdissected tis- release of stored growth factors [Vincent, 2013].
sues of joints, including articular cartilage, menis- The PCM is a specialized matrix that immedi-
cus and epiphysis, which are obtained from these ately surrounds chondrocytes and is rich in the
OA models, have advanced the molecular under- nonfibrillar type VI collagen and the heparan sul-
standing of cartilage wound healing. A cartilage fate proteoglycan perlecan, within which are
injury sets in motion a series of molecular events, sequestered various growth factors such as fibro-
which has parallels in other wounds, such as the blast growth factors (FGFs), connective tissue
expression of proteases and the release of growth growth factor, insulin-like growth factor (IGF)
factors [Martin, 1997; Wong et al. 2013]. In and members of the TGF-β superfamily such as
response to injury, there is a specific activation of activin, bone morhogenetic protein (BMP) and
inflammatory response genes in the injured their inhibitors [Vincent, 2013]. Of these, FGFs

80 http://tab.sagepub.com
 ML Tiku and HE Sabaawy

have become significant, and FGF-2 and FGF-18 clusters are formed in the middle and deep zones
are the most studied. FGF-2, through its interac- of cartilage [Brandt et al. 2008; Lotz et al. 2010].
tion with FGF receptor (FGFR)-1, promotes car- However, in spite of these reparative processes,
tilage degradation and the engagement with cartilage regrowth is generally not materialized in
FGFR-3 drives joint protection [Ellman et al. OA. The reasons for the failure of cartilage
2013]. In mouse models, FGF-2 delays cartilage regrowth are unclear. Lessons from cartilage
degradation. Mice in which the gene for FGF-2 engineering have provided additional clues; for
has been deleted develop accelerated OA sponta- example, the lateral integration of neo-cartilage to
neously and following joint destabilization adjacent cartilage is rarely observed [Huey et al.
[Chong et al. 2013]. In the human cartilage, 2012]. Also, vertical fissures in OA cartilage have
engagement of FGF-2/FGFR-1 acts as an antag- been known to fail to heal, indicting a failure of
onist by enhancing ADAMTS-5 and MMP-13 lateral integration of diseased OA cartilage tissue
induction [Ellman et al. 2013]. However, engage- [Brandt et al. 2008].
ment of FGF-18/FGFR-3 results in an anabolic
effect in human articular chondrocytes, as
reflected by increased chondrocyte viability and Directional growth of articular cartilage
cell-associated matrix formation [Ellman et al. Superficial zone chondrocytes are thought to derive
2013]. In addition to the TGF family of proteins the appositional growth of cartilage (Figure 1)
and growth factors, other factors such as Wnt sig- [Hayes et al. 2001]. This has enforced the notion
nalling molecules are also liberated following car- that articular cartilage grows from the inside of a
tilage injury [Dell’accio et al. 2008]. All of these joint cavity towards the bone. This concept is at
growth factors are involved in the normal carti- variance with the dynamics of development of
lage organogenesis and would therefore also play other tissues, such as skin and mucosal linings of
a role in OA cartilage. the gastrointestinal tract, which develop outwards
from the corresponding underlying tissues. An
Taken together, articular chondrocytes and the embryonic stem cell population treated with Gdf5
extracellular matrix participate in cartilage injury. and cyclopamine, a specific Hedgehog inhibitor,
The first task for the repair and regeneration of derived in vitro cartilage tissue, and showed zonal
cartilage is chondrocyte activation and the release organization with columnar chondrocytes at the
of cells from their locations in the matrix. This is basal layer, a collagen type II-rich tidemark, and a
achieved mainly by the release of ADAMTS-5 distinct superficial layer [Craft et al. 2013]. This
and MMP-13. Reactive oxygen radical produc- evidence indicates that cartilage can develop from
tion by activated chondrocytes may additionally the bottom up (Figure 1), suggesting that the
facilitate the breakdown of the matrix [Tiku et al. mechanisms and dynamics of articular cartilage
2000]. Once the damaged tissue is degraded, growth are still unresolved; in that regrowth may
chondrocytes with progenitor and migratory abil- occur from top or bottom or may be random.
ities populate the injured site and begin the regen- Implications of these concepts also depend on the
erative process [Morales, 2007]. In the superficial different levels of severity OA joints (Figure 2)
zone, the repair is rapidly achieved by superficial and suggest that there might be a need of a layer
zone chondrocytes. However, the breakdown and of chondrocyte-rich matrix in ulcerated lesions
regeneration of the middle zone to deeper layers that can be coaxed for regrowth.
of cartilage could be a slow process. Until recently,
it was generally believed that cartilage regenera-
tion is almost impossible in mammals. However, Distraction of OA joints helps cartilage
it has been observed in murine models that artic- regeneration
ular cartilage regeneration is heritable in that Recent investigations of the role of joint distrac-
some murine strains are robust healers while tion in OA therapy provide a clue for cartilage
other strains are nonhealers [Rai et al. 2013; Rai regeneration [Marijnissen et al. 2002; Wiegant
and Sandell, 2014]. et al. 2013]. The rationale for distracting joints is
based on the leg-lengthening surgical procedure
There is a body of evidence that shows attempts of Ilizarov. In this procedure, the broken ends of
of cartilage regeneration occurring in the middle the bone are continually distracted. The bone is
and deep zones. For example, studies in OA have then filled with cartilaginous tissue, which is later
revealed that there is an initial increase in matrix converted into bone through the bone’s healing
synthesis and cell proliferation. Chondrocyte process. The newly formed bone in the distracted

http://tab.sagepub.com 81
Therapeutic Advances in Musculoskeletal Disease 7(3)

Figure 2. Diagrams representing normal and osteoarthritic (OA) cartilage. OA cartilage is depicted as mild,
moderate and severe.

space provides solid bone tissue for lengthening of reasons. The surgical procedure for distraction
the leg. In joint distraction, it is presumed that is a serious undertaking that involves a prolonged
new cartilage tissue formed in a distracted space period of convalescence, with associated adverse
is pliable like normal cartilage and able to with- effects such as pin tract infection. This procedure
stand compression and exhibit tensile properties. usually involves joint immobilization, which can
There is some corroborative evidence indicating lead to unfavourable effects and cause atrophy of
that new cartilage tissue formed in distracted cartilage. In addition, the lack of cyclic compres-
joints exhibits cartilage-associated properties sion on the cartilage can eliminate any beneficial
[Wiegant et al. 2013]. The mechanism of cartilage anti-inflammatory and anabolic effects of mecha-
regrowth in distracted joint space is not known. notransduction on chondrocytes [Leong et al.
Moreover, factors that control tissue or organ 2011].
dimensions in the body in general are poorly
understood, except to some extent in certain
pathological conditions [Zhao et al. 2011; Monitoring cartilage degeneration and
Tumaneng et al. 2012]. Transcription co-activators regeneration
such as Yes-associated protein (YAP) and tran- The lack of consistently reliable tools to monitor
scriptional co-activator with PDZ-binding motif cartilage degeneration and regeneration has hin-
(TAZ) are known to play a role in organ size con- dered clinical studies in OA. Recent studies have
trol and regeneration, and it appears that these indicated an advantage of magnetic resonance
two processes are closely related. Also, these tran- imaging (MRI) studies of joints [Guermazi et al.
scription factors have been identified as sensors 2013]. An MRI examination can detect early
and mediators of mechanotransduction, includ- abnormalities of cartilage, ligaments, menisci,
ing in chondrocytes, suggesting that they play synovial joints, bone and bone marrow. An MRI
roles in cartilage regeneration [Dupont et al. examination shows a three-dimensional visualiza-
2011; Zhao et al. 2011; Zhong et al. 2013]. tion of cartilage and can provide quantitative,
Another possibility is that negative pressure cre- semi-quantitative and biochemical assessments of
ated in a distracted joint may accelerate cartilage cartilage. Abnormal features in an MRI can pre-
wound healing. This concept is supported by the dict rapid cartilage loss [Roemer et al. 2009,
observations of the effects of negative pressure on 2012]. These observations indicate that it is pos-
the skin wound healing process [Orgill and Bayer, sible to monitor cartilage pathology by MRI in
2013; Schluck et al. 2013]. OA [Hunter et al. 2011]. Moreover, molecular
assays, gene expression profiling and biomarkers
Although joint distraction by surgery provides a of OA severity such as microRNAs [Beyer et al.
therapeutic opportunity for OA, it may not be an 2015] could be used as secondary outcome meas-
optimum or practical undertaking for a number ures to group responders and nonresponders

82 http://tab.sagepub.com
 ML Tiku and HE Sabaawy

based on MRI studies for more qualitative meas- osteochondral defect in the weight bearing area in
ures and better understanding of the mechanisms a rabbit model of cartilage injury, therefore sug-
of repair. gesting that joint distraction may be advantageous
for cartilage regeneration [Kajiwara et al. 2005].
Distraction of osteoarthritic ankles also helps in
Paradigm of nonsurgical distraction the remodelling of subchondral bone [Wiegant
therapy of OA et al. 2013]. We believe that the paradigm pre-
Considering the aforementioned observations, we sented here merits full investigation for the treat-
suggest a study paradigm of cartilage regenera- ment of OA.
tion in OA. Patients with OA of the knee would
have MRI confirmation of their disease. According Funding
to MRI-defined qualitative, quantitative and bio- This research received no specific grant from any
chemical assessment, cartilage degeneration may funding agency in the public, commercial, or not-
be graded as mild, moderate or severe (Figure 2). for-profit sectors.
Mild disease is defined as being confined to the
upper third of the cartilage; moderate disease Conflict of interest statement
extends up to two-thirds of the cartilage, while Rutgers-Robert Wood Johnson Medical School,
severe disease extends beyond these anatomical Rutgers Cancer Institute of New Jersey, NIH, and
limits (Figure 2). Patients with mild or moderate Department of Defence generously support the
cartilage degradation, with or without osteophytes authors of this work. H.E.S. is founder and stock-
or subchondral bone lesions with compartmental holder of Celvive, Inc., a company with profiles
disease, will enter the clinical study protocol. focused on stem cell therapy technologies. M.T.
Exclusion criteria would include a history of declares no conflicts of interest in preparing this
trauma, ligament or meniscal injury, obesity, joint article.
instability or factors that could predispose to
rapid cartilage degradation. Patients in the pro-
posed pilot study will be allowed a normal wake-
up activity of the index-knee joint using knee References
unloader braces to reduce stress in the diseased Alsalameh, S., Amin, R., Gemba, T. and Lotz, M.
compartment and keep the opposing cartilage (2004) Identification of mesenchymal progenitor cells
from causing mechanical friction [Lafeber et al. in normal and osteoarthritic human articular cartilage.
2006]. During sleep, the index-knee joint will be Arthritis Rheum 50: 1522–1532.
subjected to a pull traction device to separate the Benya, P. and Shaffer, J. (1982) Dedifferentiated
bone ends of the knee joint and enhance negative chondrocytes reexpress the differentiated collagen
intra-articular pressure. It should be noted that phenotype when cultured in agarose gels. Cell 30:
sleep-time traction would sufficiently distract the 215–224.
joint. An MRI study will be repeated at 3 and 6 Beyer, C., Zampetaki, A., Lin, N., Kleyer, A.,
months of therapy or later. In a blinded manner, Perricone, C., Iagnocco, A. et al. (2015) Signature of
the baseline MRI values and values obtained at circulating micrornas in osteoarthritis. Ann Rheum Dis
the midpoint and endpoint of the study will be 74: e18.
compared. The MRI technique will provide
Blanpain, C., Horsley, V. and Fuchs, E. (2007)
sophistication and precision in measuring carti-
Epithelial stem cells: turning over new leaves. Cell
lage and bone changes, bone marrow lesions, as 128: 445–458.
well as the biochemical changes of cartilage. An
advantage of the proposed study is that it is a non- Brandt, K., Dieppe, P. and Radin, E. (2008)
invasive medical intervention and allows reason- Etiopathogenesis of osteoarthritis. Rheum Dis Clin
able daily activity. In addition, it allows joint North Am 34: 531–559.
movements and mechanotransduction of chon- Burleigh, A., Chanalaris, A., Gardiner, M., Driscoll,
drocytes without adverse effects of distraction on C., Boruc, O., Saklatvala, J. et al. (2012) Joint
cartilage growth. Recently, patellofemoral braces immobilization prevents murine osteoarthritis and
have been shown to effectively reduce symptoms reveals the highly mechanosensitive nature of protease
and bone marrow lesions in patients with patel- expression in vivo. Arthritis Rheum 64: 2278–2288.
lofemoral OA [Callaghan et al. 2015]. Furthermore, Chen, X., Macica, C., Nasiri, A. and Broadus,
studies of combination of subchondral drilling, A. (2008) Regulation of articular chondrocyte
joint motion and distraction promoted repair of proliferation and differentiation by indian hedgehog

http://tab.sagepub.com 83
Therapeutic Advances in Musculoskeletal Disease 7(3)

and parathyroid hormone-related protein in mice. cartilage and bone using stem cells from human
Arthritis Rheum 58: 3788–3797. infrapatellar fat pad. J Bone Joint Surg 85: 740–747.
Chong, K., Chanalaris, A., Burleigh, A., Jin, H., Dupont, S., Morsut, L., Aragona, M., Enzo, E.,
Watt, F., Saklatvala, J. et al. (2013) Fibroblast growth Giulitti, S., Cordenonsi, M. et al. (2011) Role of YAP/
factor 2 drives changes in gene expression following TAZ in mechanotransduction. Nature 474: 179–183.
injury to murine cartilage in vitro and in vivo. Arthritis
Dy, P., Smits, P., Silvester, A., Penzo-Mendez, A.,
Rheum 65: 2346–2355.
Dumitriu, B., Han, Y. et al. (2010) Synovial joint
Cooper, C., Dennison, E., Edward, M. and Litwic, A. morphogenesis requires the chondrogenic action
(2013) Epidemology of osteoarthitis. Medicographia of SOX5 and SOX6 in growth plate and articular
35: 145–151. cartilage. Dev Biol 341: 346–359.

Craft, A., Ahmed, N., Rockel, J., Baht, G., Alman, B., Ellman, M., Yan, D., Ahmadinia, K., Chen, D., An,
Kandel, R. et al. (2013) Specification of chondrocytes H. and Im, H. (2013) Fibroblast growth factor control
and cartilage tissues from embryonic stem cells. of cartilage homeostasis. J Cell Biochem 114: 735–742.
Development 140: 2597–2610. Fell., H. and Canti, R. (1934) Experiments on the
De Bari, C., Dell’accio, F., Tylzanowski, P. and development in vitro of the avian knee joint. Proc R
Luyten, F. (2001) Multipotent mesenchyml stem Soc Lon 116: 316–351.
cells from adult human synovial membrane. Arthritis Felson, D. (2009) Developments in the clinical under-
Rheum 44: 1928–1942. standing of osteoarthritis. Arthritis Res Ther 11: 203.
Decker, R., Koyama, E. and Pacifici, M. (2014) Callaghan, M., Parkes, M., Hutchinson,
Genesis and morphogenesis of limb synovial joints C., Gait, A., Forsythe, L., Marjanovic, E. et
and articular cartilage. Matrix Biol 39C: 5–10. al. (2015) A randomised trial of a brace for
Degen, K. and Gourdie, R. (2012) Embryonic wound patellofemoral osteoarthritis targeting knee pain
healing: a primer for engineering novel therapies for and bone marrow lesions. Ann Rheum Dis. Epub
tissue repair. Birth Defects Res C Embryo Today 96: ahead of print 16 January 2015. doi:10.1136/
258–270. annrheumdis-2014-206376.

Dell’accio, F., De Bari, C., Eltawil, N., Futami, I., Ishijima, M., Kaneko, H., Tsuji, K.,
Vanhummelen, P. and Pitzalis, C. (2008) Ichikawa-Tomikawa, N., Sadatsuki, R. et al. (2012)
Identification of the molecular response of articular Isolation and characterization of multipotential
cartilage to injury, by microarray screening: WNT- mesenchymal cells from the mouse synovium. PLoS
16 expression and signaling after injury and in One 7: e45517.
osteoarthritis. Arthritis Rheum 58: 1410–1421. Gao, Y., Lan, Y., Liu, H. and Jiang, R. (2011) The
Dell’accio, F., De Bari, C. and Luyten, F. (2001) zinc finger transcription factors OSR1 and OSR2
Molecular markers predictive of the capacity of control synovial joint formation. Dev Biol 352: 83–91.
expanded human articular chondrocytes to form stable Gossec, L., Paternotte, S., Maillefert, J.,
cartilage in vivo. Arthritis Rheum 44: 1608–1619. Combescure, C., Conaghan, P., Davis, A. et al.
(2011) The role of pain and functional impairment in
Djouad, F., Bouffi, C., Ghannam, S., Noel, D.
the decision to recommend total joint replacement in
and Jorgensen, C. (2009) Mesenchymal stem cells:
hip and knee osteoarthritis: an international cross-
innovative therapeutic tools for rheumatic diseases.
sectional study of 1909 patients. Report of the Oarsi-
Nat Rev Rheumatol 5: 392–399.
Omeract Task Force on Total Joint Replacement.
Doupe, D., Alcolea, M., Roshan, A., Zhang, G., Osteoarthritis Cartilage 19: 147–154.
Klein, A., Simons, B. et al. (2012) A single progenitor
Grogan, S., Duffy, S., Pauli, C., Koziol, J., Su, A.,
population switches behavior to maintain and repair
D’lima, D. et al. (2013) Zone-specific gene expression
esophageal epithelium. Science 337: 1091–1093.
patterns in articular cartilage. Arthritis Rheum 65:
Dowthwaite, G., Bishop, J., Redman, S., Khan, 418–428.
I., Rooney, P., Evans, D. et al. (2004) The surface
Grogan, S., Miyaki, S., Asahara, H., D’lima, D. and
of articular cartilage contains a progenitor cell
Lotz, M. (2009) Mesenchymal progenitor cell markers
population. J Cell Sci 117: 889–897.
in human articular cartilage: normal distribution and
Dowthwaite, G., Flannery, C., Flannelly, J., changes in osteoarthritis. Arthritis Res Ther 11: R85.
Lewthwaite, J., Archer, C. and Pitsillides, A. (2003) A
Guermazi, A., Roemer, F., Felson, D. and Brandt,
mechanism underlying the movement requirement for
K. (2013) Motion for debate: osteoarthritis clinical
synovial joint cavitation. Matrix Biol 22: 311–322.
trials have not identified efficacious therapies because
Dragoo, J., Samimi, B., Zhu, M., Hame, S., Thomas, traditional imaging outcome measures are inadequate.
B., Lieberman, J. et al. (2003) Tissue-engineered Arthritis Rheum 65: 2748–2758.

84 http://tab.sagepub.com
 ML Tiku and HE Sabaawy

Gunnell, L., Jonason, J., Loiselle, A., Kohn, A., Kan, A. and Tabin, C. (2013) C-Jun is required for
Schwarz, E., Hilton, M. et al. (2010) TAK1 regulates the specification of joint cell fates. Genes Dev 27:
cartilage and joint development via the MAPK 514–524.
and BMP signaling pathways. J Bone Miner Res 25:
Karlsson, C., Thornemo, M., Henriksson, H. and
1784–1797.
Lindahl, A. (2009) Identification of a stem cell niche
Hattori, S., Oxford, C. and Reddi, A. (2007) in the zone of ranvier within the knee joint. J Anat
Identification of superficial zone articular chondrocyte 215: 355–363.
stem/progenitor cells. Biochem Biophys Res Commun
Koelling, S., Kruegel, J., Irmer, M., Path, J.,
358: 99–103.
Sadowski, B., Miro, X. et al. (2009) Migratory
Hayes, A., Macpherson, S., Morrison, H., chondrogenic progenitor cells from repair tissue
Dowthwaite, G. and Archer, C. (2001) The during the later stages of human osteoarthritis. Cell
development of articular cartilage: evidence for an Stem Cell 4: 324–335.
appositional growth mechanism. Anat Embryol 203:
Koyama, E., Shibukawa, Y., Nagayama, M., Sugito,
469–479.
H., Young, B., Yuasa, T. et al. (2008) A distinct
Huey, D., Hu, J. and Athanasiou, K. (2012) Unlike cohort of progenitor cells participates in synovial joint
bone, cartilage regeneration remains elusive. Science and articular cartilage formation during mouse limb
338: 917–921. skeletogenesis. Dev Biol 316: 62–73.
Hunter, D., Zhang, W., Conaghan, P., Hirko, Lafeber, F., Intema, F., Van Roermund, P. and
K., Menashe, L., Reichmann, W. et al. (2011) Marijnissen, A. (2006) Unloading joints to treat
Responsiveness and reliability of MRI in knee osteoarthritis, including joint distraction. Curr Opin
osteoarthritis: a meta-analysis of published evidence. Rheumatol 18: 519–525.
Osteoarthritis Cartilage 19: 589–605.
Leong, D., Hardin, J., Cobelli, N. and Sun, H. (2011)
Hyde, G., Dover, S., Aszodi, A., Wallis, G. and Boot- Mechanotransduction and cartilage integrity. Ann N Y
Handford, R. (2007) Lineage tracing using matrilin-1 Acad Sci 1240: 32–37.
gene expression reveals that articular chondrocytes
Li, L. and Xie, T. (2005) Stem cell niche: structure
exist as the joint interzone forms. Dev Biol 304:
and function. Annu Rev Cell Dev Biol 21: 605–631.
825–833.
Li, T., Longobardi, L., Myers, T., Temple, J.,
Ikegawa, S., Sano, M., Koshizuka, Y. and Nakamura,
Chandler, R., Ozkan, H. et al. (2013) Joint TGF-
Y. (2000) Isolation, characterization and mapping of
beta type II receptor-expressing cells: ontogeny and
the mouse and human PRG4 (proteoglycan 4) genes.
characterization as joint progenitors. Stem Cells Dev
Cytogenet Cell Genet 90: 291–297.
22: 1342–1359.
Iwamoto, M., Ohta, Y., Larmour, C. and Enomoto-
Longobardi, L., Li, T., Myers, T., O’rear, L., Ozkan,
Iwamoto, M. (2013) Toward regeneration of articular
H., Li, Y. et al. (2012) TGF-beta type II receptor/
cartilage. Birth Defects Res C Embryo Today 99:
MCP-5 axis: at the crossroad between joint and
192–202.
growth plate development. Dev Cell 23: 71–81.
Iwamoto, M., Tamamura, Y., Koyama, E.,
Lotz, M., Otsuki, S., Grogan, S., Sah, R., Terkeltaub,
Komori, T., Takeshita, N., Williams, J. et al. (2007)
R. and D’lima, D. (2010) Cartilage cell clusters.
Transcription factor erg and joint and articular
Arthritis Rheum 62: 2206–2218.
cartilage formation during mouse limb and spine
skeletogenesis. Dev Biol 305: 40–51. Ludin, A., Sela, J., Schroeder, A., Samuni, Y., Nitzan,
D. and Amir, G. (2013) Injection of vascular endothelial
Johanson, K., Zhu, S., Tremblay, M., Payette, J.,
growth factor into knee joints induces osteoarthritis in
Wang, J., Bouchez, L. et al. (2012) A stem cell-based
mice. Osteoarthritis Cartilage 21: 491–497.
approach to cartilage repair. Science 336: 717–721.
Marijnissen, A., Van Roermund, P., Van Melkebeek,
Jones, E., Crawford, A., English, A., Henshaw, K.,
J., Schenk, W., Verbout, A., Bijlsma, J. et al. (2002)
Mundy, J., Corscadden, D. et al. (2008) Synovial
Clinical benefit of joint distraction in the treatment
fluid mesenchymal stem cells in health and early
of severe osteoarthritis of the ankle: proof of concept
osteoarthritis: detection and functional evaluation at
in an open prospective study and in a randomized
the single-cell level. Arthritis Rheum 58: 1731–1740.
controlled study. Arthritis Rheum 46: 2893–2902.
Kajiwara, R., Ishida, O., Kawasaki, K., Adachi, N.,
Martin, P. (1997) Wound healing –aiming for perfect
Yasunaga, Y. and Ochi, M. (2005) Effective repair of
skin regeneration. Science 276: 75–81.
a fresh osteochondral defect in the rabbit knee joint
by articulated joint distraction following subchondral Morales, T. (2007) Chondrocyte moves: clever
drilling. J Orthop Res 23: 909–915. strategies? Osteoarthritis Cartilage 15: 861–871.

http://tab.sagepub.com 85
Therapeutic Advances in Musculoskeletal Disease 7(3)

Morito, T., Muneta, T., Hara, K., Ju, Y., Mochizuki, magnetic resonance imaging-detected patellofemoral
T., Makino, H. et al. (2008) Synovial fluid-derived and tibiofemoral cartilage loss during a six-month
mesenchymal stem cells increase after intra-articular period: The Joints on Glucosamine Study. Arthritis
ligament injury in humans. Rheumatology 47: Rheum 64: 1888–1898.
1137–1143.
Roemer, F., Zhang, Y., Niu, J., Lynch, J., Crema,
Mundy, C., Yasuda, T., Kinumatsu, T., Yamaguchi, M., Nevitt, M. et al. (2009) Tibiofemoral joint
Y., Iwamoto, M., Enomoto-Iwamoto, M. et al. osteoarthritis: risk factors for MR-depicted
(2011) Synovial joint formation requires local fast cartilage loss over 30-month period in the
EXT1 expression and heparan sulfate production in Multicenter Osteoarthritis Study. Radiology 252:
developing mouse embryo limbs and spine. Dev Biol 772–780.
351: 70–81.
Sandell, L. (2012) Etiology of osteoarthritis: genetics
Orgill, D. and Bayer, L. (2013) Negative pressure and synovial joint development. Nat Rev Rheumatol 8:
wound therapy: past, present and future. Int Wound J 77–89.
10(Suppl. 1): 15–19.
Schindler, O. (2011) Current concepts of articular
Patra, D. and Sandell, L. (2012) Antiangiogenic and cartilage repair. Acta Orthop Belg 77: 709–726.
anticancer molecules in cartilage. Expert Rev Mol Med
Schluck, T., Nienhaus, U., Aegerter-Wilmsen, T. and
14: e10.
Aegerter, C. (2013) Mechanical control of organ size
Pazin, D., Gamer, L., Cox, K. and Rosen, V. in the development of the drosophila wing disc. PLoS
(2012) Molecular profiling of synovial joints: use of One 8: e76171.
microarray analysis to identify factors that direct the
Seol, D., McCabe, D., Choe, H., Zheng, H., Yu,
development of the knee and elbow. Dev Dyn 241:
Y., Jang, K. et al. (2012) Chondrogenic progenitor
1816–1826.
cells respond to cartilage injury. Arthritis Rheum 64:
Polk, B. and Frey, M. (2012) Mucosal restitution 3626–3637.
and repair. In: Johnson, L., Ghisban, F., Kaunitz, J.,
Spagnoli, A., O’Rear, L., Chandler, R., Granero-
Merchant, J., Said, H. and Wood, J. (eds), Physiology
Molto, F., Mortlock, D., Gorska, A. et al.
of the Gastrointestinal Tract, 5th edn, Vol. 1. London:
(2007) TGF-beta signaling is essential for joint
Academic Press, pp. 1147–1168.
morphogenesis. J Cell Biol 177: 1105–1117.
Poole, A. (2005) Cartilage in health and disease. In:
Tata, P., Mou, H., Pardo-Saganta, A., Zhao, R.,
Koopman, W. and Moreland, L. (eds), Arthritis &
Prabhu, M., Law, B. et al. (2013) Dedifferentiation
Allied Conditions: A Textbook of Rheumatology, 15th
of committed epithelial cells into stem cells in vivo.
edn. Philadelphia, PA: Lippincott Williams, Wilkins,
Nature 503: 218–223.
pp. 223–269.
Tiku, M., Shah, R. and Allison, G. (2000) Evidence
Poole, A., Rosenberg, L., Reiner, A., Ionescu, M.,
linking chondrocyte lipid peroxidation to cartilage
Bogoch, E. and Roughley, P. (1996) Contents and
matrix protein degradation. Possible role in cartilage
distribution of proteoglycans decorin and biglycan in
aging and the pathogenesis of osteoarthritis. J Biol
normal and osteoarthritic human articular cartilage.
Chem 275: 20069–20076.
J Orthopaed Res 14: 681–689.
Tumaneng, K., Russell, R. and Guan, K. (2012)
Pretzel, D., Linss, S., Rochler, S., Endres, M., Kaps,
Organ size control by Hippo and TOR pathways. Curr
C., Alsalameh, S. et al. (2011) Relative percentage
Biol 22: R368–379.
and zonal distribution of mesenchymal progenitor
cells in human osteoarthritic and normal cartilage. Vertel, B. (1995) The ins and outs of aggrecan. Trends
Arthritis Res Ther 13: R64. Cell Biol 5: 458–464.
Rai, M. and Sandell, L. (2014) Regeneration of Verzijl, N., Degroot, J., Thorpe, S., Bank, R., Shaw,
articular cartilage in healer and non-healer mice. J., Lyons, T. et al. (2000) Effect of collagen turnover
Matrix Biol 39: 50–55. on the accumulation of advanced glycation end
products. J Biol Chem 275: 39027–39031.
Rai, M., Schmidt, E., Mcalinden, A., Cheverud, J.
and Sandell, L. (2013) Molecular insight into the Vincent, T. (2013) Targeting mechanotransduction
association between cartilage regeneration and ear pathways in osteoarthritis: a focus on the pericellular
wound healing in genetic mouse models: targeting matrix. Curr Opin Pharmacol 13: 449–454.
new genes in regeneration. G3 (Bethesda) 3:
Watt, F., Ismail, H., Didangelos, A., Peirce, M.,
1881–1891.
Vincent, T., Wait, R. et al. (2013) Src and fibroblast
Roemer, F., Kwoh, C., Hannon, M., Green, S., growth factor 2 independently regulate signaling
Jakicic, J., Boudreau, R. et al. (2012) Risk factors for and gene expression induced by experimental injury

86 http://tab.sagepub.com
 ML Tiku and HE Sabaawy

to intact articular cartilage. Arthritis Rheum 65: Zhang, Q., Cigan, A., Marrero, L., Lopreore,
397–407. C., Liu, S., Ge, D. et al. (2011) Expression of
doublecortin reveals articular chondrocyte lineage
Wiegant, K., Van Roermund, P., Intema, F.,
in mouse embryonic limbs. Genesis 49:
Cotofana, S., Eckstein, F., Mastbergen, S. et al.
75–82.
(2013) Sustained clinical and structural benefit after
joint distraction in the treatment of severe knee Zhao, B., Tumaneng, K. and Guan, K. (2011)
osteoarthritis. Osteoarthritis Cartilage 21: 1660–1667. The Hippo Pathway in organ size control, tissue
Wilusz, R., Sanchez-Adams, J. and Guilak, F. (2014) regeneration and stem cell self-renewal. Nat Cell Biol
The structure and function of the pericellular matrix 13: 877–883.
of articular cartilage. Matrix Biol 39: 25–32.
Zhong, W., Li, Y., Li, L., Zhang, W., Wang, S.
Wong, V., Gurtner, G. and Longaker, M. (2013) and Zheng, X. (2013) YAP-mediated regulation of Visit SAGE journals online
http://tab.sagepub.com
Wound healing: a paradigm for regeneration. Mayo the chondrogenic phenotype in response to matrix
Clin Proc 88: 1022–1031. elasticity. J Mol Histol 44: 587–595. SAGE journals

http://tab.sagepub.com 87