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 DOI: 10.5772/intechopen.72496
Chapter 4
Provisional chapter

Osteoarthritis of the Temporomandibular Joint: Clinical

Osteoarthritis of the Temporomandibular Joint: Clinical
and Imagenological Diagnosis, Pathogenic Role of the
and Imagenological Diagnosis, Pathogenic Role of the
Immuno-Inflammatory Response, and
Immuno-Inflammatory Response, and Immunotherapeutic
Immunotherapeutic Strategies Based on T Regulatory
Strategies Based on T Regulatory Lymphocytes
Lymphocytes

Gustavo Monasterio, Francisca Castillo, Daniel Betancur,

Gustavo Monasterio, Francisca Castillo,
Arnoldo Hernández, Guillermo Flores, Walter Díaz,
Daniel Betancur, Arnoldo Hernández,
Marcela Hernández and Rolando Vernal
Guillermo Flores, Walter Díaz,
Marcela Hernández
Additional information and Rolando
is available Vernal
at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72496

Abstract

Osteoarthritis is a degenerative disease affecting the TMJ. It is the most common TMJ
disorder and shows a higher prevalence in women and older people. TMJ osteoarthritis
(TMJ-OA) is characterized by variable degrees of inflammation, destruction of the articu-
lar cartilage, and sub-chondral bone resorption. In this context, diverse pro-inflammatory
cytokines, chemokines, enzymes, and bone-resorptive associated factors have been con-
sidered as possible markers of active TMJ-OA. The molecular balance is determinant
not only for initiation and progression, but also for the clinical expression of the disease.
Recent advances in the biochemical analysis of synovial fluid from affected patients have
provided new insights into the patho-physiology of the TMJ-OA; however, its molec-
ular pathogenesis still remains unclear. Recently, a Th1 and Th17-dominated immune
response has been associated with the inflammatory and destructive events character-
istic of TMJ-OA and, in particular, the Th17 lymphocyte pathway has a pivotal role in
the increased production of RANKL, which is involved in osteoclast activation and sub-
sequent sub-chondral bone resorption. Understanding the TMJ physiology and patho-
genesis of the TMJ-OA, together with the key molecular determinants of the TMJ tissue
destruction, will enable the development of new chair-side point of care diagnostics and
more conservative treatment modalities with minimal complications.

Keywords: osteoarthritis, temporomandibular joint, pathogenesis, diagnosis,

immunotherapy, Treg cells

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly cited.
70 Temporomandibular Joint Pathology - Current Approaches and Understanding

1. Introduction

The temporomandibular joint (TMJ) is the movable articulation of the bone head. Its structure
and morphology share common features with other synovial joints; however, it also presents
particularities that make it unique. In fact, deep knowledge of the anatomy and function of the
TMJ is a central challenge for clinicians and scientists, since many of the pathological condi-
tions that affect this articulation can be explained based on its morphological and physiologi-
cal aspects.

2. Temporomandibular joint: anatomical characteristics

The TMJ is a synovial joint composed of two articular surfaces [1–4] (Figure 1). The inferior
articular surface is given by the mandibular articular surface, which is part of the mandibular
head. Structurally, the mandibular head is formed by two surfaces, anterior and posterior,
both separated by a ridge that follows the same axis of the mandibular head [5–7]. The ante-
rior portion of the mandibular head is relatively convex in contrast with the posterior surface
which is characterized for being flat and vertical [7, 8] (Figure 2). On the other hand, the
superior articular surface of the TMJ is given by the horizontal portion of the squama of the
temporal bone, which is organized forming two highly relevant structures: the mandibular
fossa and the articular eminence of the temporal, also called temporal condyle [1, 2, 7–11].
The mandibular fossa corresponds to a concave surface with its greater axis in the transverse
diameter [2, 7, 8, 12] and the temporal condyle corresponds to a convex bony elevation with
its major dimension at the transverse axis, formed by an anterior and posterior surfaces with-
out a clear boundary between the two of them [8, 9, 11]. Additionally, in the TMJ, it is possible

Figure 1. Anatomical characteristics of the temporomandibular joint (TMJ). Sagittal section of TMJ. Mandibular head
(MH) articulating with temporal condyle (TC) and mandibular fossa (MF). Between the two joint surfaces the articular
disc (AD) is interposed. The middle portion of the thinner disc portion being located in the work area; the anterior
articular disc is continuous with the fibers of the lateral pterygoid muscle (LP), which is also inserted into the pterygoid
fossa (PF) of the mandibular condyle neck; the back of the disc is related to the vascularized tissue in the retrodiscal
area (RA). TMJ localizes superior to the middle cranial fossa (MCF) and posterior to the internal auditory canal (IAC).
 Osteoarthritis of the Temporomandibular Joint: Clinical and Imagenological Diagnosis… 71
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Figure 2. Anatomical characteristics of the temporomandibular joint. (A) Lateral, (B) frontal, and (C) superior view of
the mandibular head. This is formed by two poles, the lateral pole (LP) and the medial pole (MP), the latter being larger.
In a side view, it is possible to observe the morphology of the anterior surface (AS) (convex) and posterior surface (PS)
(flat) of the mandibular head. In the lower portion of the mandibular head at its point of junction with the condylar neck
(CN), the pterygoid fossa can be seen (PF), where the lateral pterygoid muscle is inserted.

to observe an articular disc, which allows fitting the temporal condyle and the mandibular
head [1, 5]. It is avascular and not innervated at its center, which coincides with the area of
greatest work [2, 6, 8, 13]. Like the mandibular fossa and head, its greater dimension is at the
transverse axis and adapts closely to the adjacent surfaces [2, 6–8].

3. Temporomandibular joint: physiological characteristics

Mandibular movements are limited by a number of structures, which actively or passively

avoid excessive mandibular displacement and consequently limit the movements within the
joint. The main protective and customizing element of the joint complex relates to the joint
­capsule. This structure consists of thick organized bundles of collagen fibers that are uphol-
stered with several proprioceptors that report changes in mandibular dynamics, thereby limit-
ing the mandibular border movements [6]. Anteriorly, the capsule is inserted in the articular
eminence [7, 8]. Laterally, the capsule strongly adheres to the longitudinal root of the zygoma
and is continued backwards in tympanosquamous fissure [7, 8, 14]. The medial insertion is less
extensive, inserted mainly in the sphenoid spine. The inferior insertion of the capsule extends
along the condyle neck as a ring that is down on the backside of condylar process neck [7, 8, 14].
72 Temporomandibular Joint Pathology - Current Approaches and Understanding

There is a set of ligaments that meet a similar role to the capsule, functionally and structurally
reinforcing the TMJ [6–8]. The main reinforcement ligament capsule corresponds to temporo-
mandibular ligament which is located lateral to it. From this point of insertion the temporo-
mandibular ligament lateral band descends obliquely and posteriorly, and finally inserts onto
the posterior surface of condylar neck [7]. The medial band is horizontal, presenting a similar
cranial origin to the lateral band, and is inserted into the lateral side of the mandibular head
[11]. Portions of the temporomandibular ligament execute a different role within the man-
dibular dynamics [6].
Additionally, there are a number of ligaments in the TMJ that are not structural or for its rein-
forcement, however limit the mandibular dynamics and hence the joint function. The stylo-
mandibular, sphenomandibular, pterygomandibular and pterygospinous ligaments meet this
role [7, 14]. The stylomandibular ligament is a segment of the muscular structures and it is
originated in the styloid process forming the styloid bouquet [7]. Since its origin, the styloman-
dibular ligament descends obliquely to finally insert on the posterior and inferior border of
the ramus. In the case of the sphenomandibular ligament, this appears as a thickening of the
interpterygoid fascia, which inserts cranially into the sphenoid spine and in the mandibular
lingula [7, 14, 15]. Its thickness and extent varies between the individuals and in its upper por-
tion penetrates into the middle ear throughout the petrotympanic fissure being continued as
the anterior ligament of the malleus [10, 16–18]. The pterigomandibular ligament originates
from the pterygoid hamulus of the medial lamina of the pterygoid process of the sphenoid
bone and from that point is inserted into the lateral lip of the mandibular retromolar trigone
[7]. It is inserted in the buccinator muscles anteriorly and the superior constrictor muscle of
the pharynx posteriorly. Finally, the pterygoespinous ligament, like the sphenomandibular,
corresponds to a thickening of the interpterygoid fascia. It is reported that this ligament may
undergo calcifications, which could produce alterations in the transmission of the mandibular
nerve, because of its intimate relationship with the mandibular foramen determining nerve
compression [19].

4. TMJ-OA: clinical classification and diagnosis

Temporomandibular disorders (TMDs) are the most widely accepted term to designate the mus-
culoskeletal alterations of the TMJs. All TMDs share similar signs and symptoms, traditionally
described as a triad of pain (TMJs, muscles, and tooth pain), interferences during mandibular
movement (frequently associated with joint noises), and/or movement range limitation [20]. Bell
developed the first classification of TMDs in 1986, and it was based on an orthopedic-mechanical
model [21]. This classification was composed of four major categories (masticatory pain, restric-
tion of mandibular movements, joint interference during mandibular movements, and acute
malocclusion) and identified five muscular processes (myositis, muscle spasm, ­myofascial pain,
late-onset muscle irritation, and protective co-contraction or protective stiffness). However, it
was not until 1990 that the American Academy of Craniomandibular Disorders (AACD), along
with the International Headache Society (IHS), developed the first taxonomic system of classifi-
cation [22]. The main contributions were the distinction of two major categories (joint disorders
and muscle disorders) and the possibility of establishing multiple diagnoses.
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In 1992, a new taxonomic classification system was developed and termed “The Research
Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD)” [23]. This system was
based on the biopsychosocial model of pain, and included the Axis I (physical assessment
using reliable and well-operationalized diagnostic criteria), and Axis II (assessment of psy-
chosocial status and pain-related disability) [23]. The main purpose of this classification
system was to establish standardized criteria for research, and to provide simultaneously a
physical diagnosis in order to identify other patients’ characteristics that could modify the
expression and eventually the management of their TMD [22].
Since 2014, the new DC/TMD Axis I and Axis II provide an evidence-based assessment pro-
tocol also based on the biopsychosocial model (Figure 3) that can be directly applied in the
clinical and research setting [24]. In this consensus, the information required for fulfilling the
Axis I diagnostic criteria is obtained from a specified examination protocol in conjunction
with the core self-report instruments that assess pain symptoms involving the jaw, jaw noise
and locking, and headache. Axis II core assessment instruments assess pain disability, pain
intensity, jaw functioning, parafunctional behaviors, psychosocial distress, and widespread
pain. All of these incorporations and changes in the core patient assessment instrument set
serve as a broad foundation for patient assessment and further research [24].
The DC/TMD also includes changes to original RDC/TMD TMJ diagnoses. An important con-
sideration was the low sensitivity for the diagnostic algorithms for disc displacement (DD) and
degenerative joint disease (DJD) (osteoarthritis and osteoarthrosis) in RDC/TMD that can pro-
vide only provisional diagnoses [24]. This is due to the fact that some DD with reduction do not
have clinically detectable noise, and the disorder will not be diagnosed using the clinical criteria

Figure 3. Biopsychosocial model of disease applied to temporomandibular disorders. Axis I refers to the severity of the
patient’s biological factors, including physical disorders. Axis II refers to the severity of psychosocial and behavioral factors,
including interference in functioning because of pain. Two possible types of patients are depicted, each situated according
to disease severity on the respective axes: Patient A has a mechanical temporomandibular joint (TMJ) disorder without
secondary factors; and patient B has a pain diagnosis and clinically significant disruption in overall function and mood.
74 Temporomandibular Joint Pathology - Current Approaches and Understanding

(positive history of noise and the presence of clicking noises) [25]. DD with reduction is highly
prevalent, and crescent data suggest that internal derangement, such as DD with reduction, is
likely to progress to osteoarthritis [20, 26, 27]. However, based on the evidence, DD with reduc-
tion is probably without clinical consequences unless pain occurs with noises or functional
limitations, such as limited opening or interference in mastication. Nonetheless, the DC/TMD
suggests that imaging using MRI is required for a definitive diagnosis of TMJ DD [24].
The differential diagnosis with the other TTMs is very important in the clinical assessment.
The DC/TMD taxonomic classification for TMDs is divided in four major groups: temporo-
mandibular joint disorders, masticatory muscle disorders, headache, and associated structures.
Of these, the temporomandibular joint disorders main group includes two subtypes of joint
pain, three subtypes of joint disorders, and seven different subtypes of joint disease (Table 1).
The clinical procedures to evaluate DD with reduction, DD without reduction without limited
opening, and DJD lead to clinical diagnoses based on procedures that exhibit low sensitivity
but well to excellent specificity. Thus, for treatment decision in selective cases, confirmation of
presumptive diagnostic requires imaging. In contrast, clinical algorithm for assessing DD with-
out reduction with limited opening has good sensitivity and specificity (80 and 97%, respec-
tively) [28], being enough with the clinical evaluation for the initial working diagnosis [24].
DC/TMD made some changes to the diagnostic procedures of RDC/TMD for DD and DJD. TMJ
noise by history is one of the recommended criteria for the intra-articular disorders of DD
with reduction and DJD. The patient’s report of any joint noise (click or crepitus) during the
30  days prior to examination should be met by the history criterion or the patient’s detec-
tion of any joint noise with jaw movements during the clinical examination. Furthermore,
DD with reduction diagnosis requires examiner detection of clicking, popping, or snapping
noises during examination. In DJD diagnosis requires examiner detection of crepitus (e.g.,
crunching, grinding, or grating noises) during the examination, and distinction between fines
versus coarse crepitus is not necessary. For DD without reduction, the subtype depends on an
assisted opening measurement (including the amount of vertical incisal overlap): if is <40 mm
it is “with limited opening” subtype, and if is ≥40 mm it is “without limited opening” subtype.
In this category, joint noise does not affect the diagnosis of DD without reduction as long as
the required criteria for DD without reduction are met (Table 2) [24].
The DJD includes osteoarthritis and osteoarthrosis (Table 1). While the DD with reduction
was described as “An intracapsular biomechanical disorder involving the condyle-disc complex. In
the closed mouth position, the disc is in an anterior position relative to the condylar head and the disc
reduces upon opening of the mouth. Medial and lateral displacement of the disc may also be present.
Clicking, popping, or snapping noises may occur with disc reduction. A history of prior locking in
the closed position coupled with interference in mastication precludes this diagnosis,” the description
given by the DC/TMD to DJD is “A degenerative disorder involving the joint characterized by dete-
rioration of articular tissue with concomitant osseous changes in the condyle and/or articular eminence”
[24]. The diagnostic criteria for these conditions demand a meticulous anamnesis and clinical
examination. The DJD diagnosis is considered positive when either the patient reports any
TMJ noise in the last 30 days (during mastication or any jaw movement) or the clinician detects
any noise during mandibular movements. In addition, the DJD diagnosis is associated with
clinical detection of TMJ crepitus during palpation, when patient is doing opening, closing,
lateral, or protrusive mandibular movements. These important differences along exploration
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I. Temporomandibular joint disorders

a. Joint Pain

  i. Arthralgia

  ii. Arthritis

b. Joint Disorders

  i. Disc disorders

   1. Disc displacement with reduction

   2. Disc displacement with reduction with intermittent locking

   3. Disc displacement without reduction with limited opening

   4. Disc displacement without reduction without limited opening

  ii. Hypomobility disorders other than disc disorders

   1. Adhesions/adherence

   2. Ankylosis

    a. Fibrous

    b. Osseous

  iii. Hypermobility disorders

   1. Dislocations

    a. Subluxation

    b. Luxation

c. Joint diseases

  i. Degenerative joint disease

   1. Osteoarthrosis

   2. Osteoarthritis

  ii. Systemic arthritides

  iii. Condylysis/idiopathic condylar resorption

  iv. Osteochondritis dissecans

  v. Ostronecrosis

  vi. Neoplasm

  vii. Synovial chondromatosis

d. Fractures

e. Congenital/developmental disorders

  i. Aplasia

  ii. Hypoplasia

  iii. Hyperplasia

Table 1. DC/TMD taxonomic classification for temporomandibular disorders (only TMJ disorders).
76 Temporomandibular Joint Pathology - Current Approaches and Understanding

History

a. In last 30 days, any noise present” applicable to disc displacement with reduction with and without intermittent
locking, and degenerative joint disease.

b. In last 30 days, jaw locks with limited mouth opening and then unlocks” applicable to disc displacement with
reduction with intermittent locking.

c. “Ever has jaw lock or catch so that it would not open all the way” and “interfered with eating” applicable to disc
displacement without reduction with and without limited opening.

d. In last 30 days, when you opened your mouth wide, jaw locked or caught so that it would not close all the way”
applicable to subluxation.

Examination

i. Disc displacement with reduction.

1. Report by patient of any joint noise (click or crepitus).

2. Click detection (# of opening/closing cycles required for click) (1 of 3).

3. Click detection during lateral and protrusive movements.

ii. Disc displacement with reduction with intermittent locking.

iii. Disc displacement without reduction with limited opening.

1. Assisted opening* < 40 mm.

iv. Disc displacement without reduction without limited opening.

1. Assisted opening* ≥ 40 mm.

v. Degenerative joint disease.

1. Report by patient of any joint noise (click or crepitus).

2. Crepitus (either fine or coarse) with palpation.

*
Measurement of opening includes interincisal opening plus vertical incisal overlap.

Table 2. DC/TMD diagnostic procedures for disc displacements and degenerative joint disease with new history-based
diagnosis of subluxation.

were not reported in the RDC/TMD previous consensus, which only included coarse crepitus
detected by the examiner’s palpation. Nevertheless, the sensitivity and specificity of these cri-
teria are 55 and 61%, respectively, being the imaging the reference standard for this diagnosis.
In particular, the diagnosis confirmation suggest by DC/TMD is with TMJ CT [24].

In summary, the DC/TMD assessment protocol has both screening and confirmatory tests
for the most common Axis I physical diagnoses and for Axis II contributing factors (Table 3).
However, an important remark is the poor diversity of diagnostic tools available until now.
The DC/TMD raise a useful systematic imagenological and clinical diagnostic tool, but with no
usefulness in the study of disease progression and/or prediction. Several studies suggest some
biological markers of degenerative joint disease, such as certain cytokines or proinflammatory
mediators [29–42], and could be useful in the elaboration of complementary tools for diagnos-
tic purposes with potential in the study of disease prediction/progression. Thereby, the devel-
opment of diagnostic/prognostic devices based on these molecular markers is an interesting
research field that could significantly improve the precision of osteoarthritis diagnosis.
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Axis I: Physical diagnosis Axis II: Psychosocial status

Pain diagnoses Joint diagnoses Distress and pain disability

Application Clinical or research Clinical Clinical or research

Screening test TMD pain DC/TMD for disc PHQ-4 and GCPS PHQ-9, GAD-7,
screener displacements, PHQ-15, and GCPS
degenerative joint disease,
and subluxation

Confirmatory test DC/TMD Imaging: MRI for disc Consultation with mental Structured
for myalgia, displacements, CT health provider psychiatric or
arthralgia, for degenerative joint behavioral medicine
and headache disease, and panoramic interview
attributed to radiographs, MRI, or CT
TMD for subluxation

Patient Health Questionnaire-4 (PHQ-4), Graded Chronic Pain Scale (GCPS), Patient Health Questionnaire-9 (PHQ-9),
Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-15 (PHQ-15).

Table 3. Clinical and research applications of selected DC/TMD Axis I and Axis II tests.

5. TMJ-OA: imagenological characteristics

Computed tomography (CT) and magnetic resonance (MRI) are widely useful tools for imaging the
TMJ region of TMD patients, in particular for assessing degenerative bony changes, disc position
and configuration, inflammatory pathological changes in the posterior disc attachment, the presence
of effusion in joint spaces, and bone marrow edematous involvement [43]. Cone beam computed
tomography (CBCT) allows the visualization of the TMJ in all three planes with high resolution,
minimal distortion, and great precision for identifying condylar cortical changes [44]. The TMJ imag-
ing by CBCT also allows the evaluation of the integrity of the bony structures when a degenerative
disease is suspected, and to confirm the extent and progression of any bony changes [45].
The degenerative changes of bone in DJD are more frequent in the mandibular condyle than
in the mandibular fossa or the articular eminence, and the characteristic pathological bony
changes are erosion, osteophytes, and deformity; and adaptive bony changes are marginal
proliferation, flattening, concavity, sclerosis, and sub-chondral cyst [46–49]. All of these
anomalies are considered, for diagnostic purposes, as signs of osteoarthritis and frequently
are observed in joints with long-standing DD without reduction [47].
Some imaging technologies such as CT [49–51], CBCT [46, 52, 53], and MR [47, 54–56] have
been widely used for diagnosing DJD such as TMJ osteoarthritis. However, is CBCT, a fairly
new imaging technology, that has the possibility to create images of high diagnostic quality
using lower radiation doses than CT [53]. CBCT imaging has shown to be very helpful for
depicting abnormal bony changes such as the cortical margin of the surface and sub-chondral
cancellous trabecular structure present in the mandibular condyle, where the conventional
radiography has shown difficulties to analyze successfully [30]. Conventional tomography
also has difficulties in detailed assessment of changes in the surface morphology of the con-
dyle and fossa, due to the thickness of the slices (1.0–3.0 mm) [57].
78 Temporomandibular Joint Pathology - Current Approaches and Understanding

Another interesting imaging technique for the diagnosis of TMJ osteoarthritis evaluated in
the evidence is the bone scintigraphy [58–61]. This technique shows a correlation with signs
and symptoms with very good sensitivity, specificity, and accuracy (100, 90.91, and 96.97%,
respectively) [59]. Interestingly, some radiographic changes seen by follow-up CBCT, MRI,
and scintigraphy suggested that osteonecrosis may be the initial phase of an osteoarthritic
process [30]. Thus, knowing all the potential imaging findings of every imaging modality is
very important to make right imaging diagnostics (Table 4).

Imaging modality Imaging findings

Medical CT and cone beam CT Pathological bony changes such as erosion, osteophyte and
deformity

Osteochondritis disseccans

Static MR imaging Disc positional abnormalities

 (1) DD without reduction

 (2) DD with reduction

 (3) Sideways disc displacement

Joint effusion presence of marked effusion

A higher T2 signal of the posterior disc attachment

Bone marrow abnormalities

 (1) Bone marrow edema

 (2) Bone marrow osteonecrosis

Tumor involvement and inflammatory diseases into the TMJ

region and the surrounding structures

Autoimmune processes such as rheumatoid arthritis

A closer proximity between the TMJ disc and the mandibular nerve

Dynamic MR imaging with contrast material Prominent contrast enhancement of the posterior disc attachment

Contrast enhancement of effusion

Magnetization transfer contrast imaging Detection for the edematous and ischemic changes in the muscles

Magnetic resonance spectroscopy Ascending of insular glutamine levels by 1H MRS

Functional MR imaging The regions and the network of brain activation associated
with TMD

Ultrasonography Muscular edema by low-level contraction

Bone scintigraphy Detection for early changes on the osseous reaction of OA

TMJ, temporomandibular joint; MM, masticatory muscle; DD, disc displacement; TMD, temporomandibular disorders;
OA, osteoarthritis.

Table 4. A rating of the usefulness of each imaging modality related to TMJ pain, MM pain and fatigue.
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When the clinical diagnosis of DD with reduction or with reduction with intermittent locking
needs imaging confirmation, the DC/TMD suggests positive detection of the following: “(1)
in the maximum intercuspal position, the posterior band of the disc is located anterior to the 11:30
position and the intermediate zone of the disc is anterior to the condylar head; and (2) on full opening,
the intermediate zone of the disc is located between the condylar head and the articular eminence” [24].
Otherwise, the imaging confirmation criteria by TMJ MRI of DD without reduction with/with-
out limited opening clinical diagnosis are: “(1) in the maximum intercuspal position, the posterior
band of the disc is located anterior to the 11:30 position and the intermediate zone of the disc is anterior
to the condylar head; and (2) on full opening, the intermediate zone of the disc is located anterior to the
condylar head (Note: Maximum assisted opening of < 40 or ≥ 40 mm is determined clinically)” [24].

Figure 4. Imagenological characteristics of the temporomandibular joint affected with osteoarthritis. (A) Sagittal CBCT
images of a TMJ of a patient with DC/TMD diagnosis of osteoarthritis but without bony osteoarthritic changes (erosions
and osteophytes). (B) Sagittal CBCT images of a TMJ of a patient with a DC/TMD diagnosis of osteoarthritis and with bony
osteoarthritic changes (erosions and osteophyte). CBCT: Cone beam computed tomography, TMJ: temporomandibular
joint, DC/TMD: diagnostic criteria for temporomandibular joint. White arrow: osteophyte; black arrow: flattening; dot
pattern arrow: erosion; asterisk: sclerosis.
80 Temporomandibular Joint Pathology - Current Approaches and Understanding

The DC/TMD criteria consider a positive diagnostic of DJD when the TMJ-CBCT is positive for at
least one of the following: sub-chondral cyst(s), erosion(s), generalized sclerosis, or osteophyte(s).
An important difference between RDC/TMD and DC/TMD is in flattening and/or cortical sclero-
sis, because while the first consider as positive findings, the second consider indeterminate find-
ings and possible sign of normal variation, aging, remodeling, or a precursor to frank DJD [24].
The great sensitivity and specificity of TMJ-CBCT in the DJD diagnoses compared with the clin-
ical assessment was well demonstrated in the work of Bakke et al., that shows 21 TMJ-CBCTs
positive for osteoarthrosis while only two were clinically positive for the disease [62]. The high
frequencies of bony changes in the CBCT images of pain-free subjects in this study were in
accordance with the findings of Krisjane et al. indicating that radiographic signs of ­osteoarthritis
are a poor indicator of pain [63]. Furthermore, several studies have demonstrated that there is
a poor correlation between condylar bony changes including pathological changes, ­adaptive
changes and/or remodeling and pain symptoms in TMJ osteoarthritis [55, 56, 64–66]. These
results support the idea that many times the bony changes are not associated with the clinical
diagnoses (Figure 4), and that good diagnoses comprehend history of the patient, and clinical/
imaging diagnostic, although, new assessment tools are necessary for accuracy of the diagnoses.

Figure 5. Diagnostic criteria for temporomandibular disorders (DC/TMD): diagnostic decision tree. Schematic diagnostic
decision tree made to summarize the algorithm of diagnostic for intra-articular disorders (disc displacement with
reduction, disc displacement with reduction with intermittent locking, disc displacement without reduction with limited
opening, or disc displacement without reduction without limited opening), or degenerative joint disease (osteoarthritis
or osteoarthrosis), including history, clinical examination, and imaging.
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Finally, Figure 5 shows the decision tree made in the DC/TMD consensus summarizes the
algorithm made for the diagnosis of degenerative joint disease and intra-articular joint disor-
ders with history, clinical, and imagenological features.

6. Role of the immuno-inflammatory response in the pathogenesis of

the TMJ-OA

TMJ-OA is a disease having a great deal of variation in progression, symptoms, epidemiol-

ogy, pathophysiology, and presentation. The rate of progression from a healthy joint to a
severe TMJ-OA can vary from weeks to decades and TMJ-OA affects all of the tissues of the
joint, including the articular cartilage, synovium, sub-chondral bone, capsule, ligaments, peri-
articular muscles, and the sensory nerves innervating the tissues.

Many factors have been proposed as responsible for the TMJ-OA development, such as genetic
factors, over-loading, unilateral chewing, bruxism, and internal derangement; however, the
molecular basis of the TMJ-OA aetio-pathogenesis remains unclear [67–70].

During TMJ-OA, a complex inflammatory response is developed, involving the synthesis of

different cytokines by resident cells (e.g., synovial fibroblast, chondrocytes, and macrophages)
and inflammatory cells that infiltrate the joint tissues [71, 72]. This inflammatory response
could be triggered as result of the tissue breakdown and the consequent release of damage-
associated molecular patterns (DAMPs), such as low molecular weight hyaluronan (LMW-HA),
high-mobility group protein 1 (HMGB1), and S100 proteins [73, 74], activating resident inflam-
matory cells, including dendritic cells and macrophages [75]. At initial stages of the disease,
functional overload induces oxidative stress that initiates cartilage disruption [76, 77] and acti-
vation of MMPs and aggrecanases, promoting the secretion of DAMPs and the activation of
the immune response [75]. During the disease progression, there is a local imbalance between
the expression of specific cytokines, their receptors, and regulatory soluble receptors, which
may be critical in the biological activity of the cytokine network [35]. Under these conditions,
both fibroblast and synovial cells are activated to express MMPs and bone-associated cyto-
kines that control the formation/destruction of articular cartilage and bone, determining the
clinical outcome of the OA-TMJ (Figures 6 and 7). In fact, higher levels of interleukin (IL)-1β,
IL-6, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, prostaglandin E2 (PGE2), matrix
metalloproteinase (MMP)-2, MMP-9, aggrecanase-1, superoxide dismutase, substance P, and
receptor-activator of nuclear factor-κB ligand (RANKL) have been detected in synovial fluid
from TMJ-OA patients as compared with disc displacement with reduction (DDWR), disc dis-
placement without reduction (DDWOR), or healthy subjects Table 5 [35, 40, 42, 68, 69, 78–86].

Certain cytokines such as IL-1β, IL-6, and TNF-α has been associated with signs and symp-
toms of TMJ-OA, in particular, synovitis and arthralgia [39]. In addition, TNF-α and IL-6
have been described as markers of pain and successful clinical outcomes in TMDs [87, 88].
However, a study assessing the relation between the scores from a visual analog scale of pain
and the levels of IL-1β, IL-6, and TNF-α reported no positive correlation [35]. Differences
among different studies results could be due to variability in the selection criteria of subjects,
sampling techniques, and/or analysis methods.
82 Temporomandibular Joint Pathology - Current Approaches and Understanding

Figure 6. Phases in progression of the degenerative joint disease of the temporomandibular joint. (1) Fibrocartilage and
bone tissue in physiological state, (articular disc in correct position). (2) The presence of functional overload or individual
susceptibility generates hypoxia and compression of the articular tissues, resulting in apoptosis of chondrocytes and
fibroblasts of the fibrocartilage, and DAMP’s release, such as ATP, ROS, TIMPs, fragments of collagen and low molecular
weight hyaluronic acid. In addition to cytokines and chemokines, these molecules produced by synoviocytes allow the
migration of immune cells into the joint, such as dendritic cells that generate the environment leading to the polarization of
T cell populations towards Th1, Th22, and Th17 phenotypes. These polarized cells in turn will allow the differentiation and
activation of osteoclasts that will degrade the articular surface establishing the degenerative and destructive pathology (3).

IL-17 plays a key role in the pathogenesis of rheumatoid arthritis by inducing the syn-
oviocyte-dependent IL-6 secretion [89]. In addition, TNF-α and IFN-γ augment the IL-17
activity and IL-17 activity has been associated with synovitis, chondral degradation, and
inhibition of chondrocyte proliferation [89]. The presence of IL-17  in the TMJ synovial
 Osteoarthritis of the Temporomandibular Joint: Clinical and Imagenological Diagnosis… 83
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Figure 7. Chemotaxis of immune cells to the subarticular space. Synoviocytes, fibroblasts and chondrocytes produce
cytokines, chemokines, intracellular DAMPs, and extracellular matrix derivatives that facilitate the migration of immune
cells from the bloodstream into the joint. VEGF and CCL5 facilitate the overexpression of CD44 in endothelial cells and
T cells. These molecules, together with low molecular weight hyaluronic acid fragments (sandwich effect), facilitate the
diapedesis of lymphocytes through the vessels, enhancing the inflammatory stage of the disease in progress.

fluid could be an important pathophysiological biomarker of TMJ-OA [40]. In fact, bone

resorption associated with an increased osteoclast activity is a central phenomenon in
the pathophysiology of autoimmune and inflammatory arthritis, and it is also related to
IL-17 presence, mainly through T lymphocyte-associated direct and indirect regulation [90,
91]. RANKL is the main molecule involved in the direct regulation of osteoclast activity,
through the direct activation of osteoclast precursors [92]. Conversely, the indirect regula-
tion depends on the secretion of IL-17, IL-1β, and TNF-α by synoviocytes, cytokines that in
84 Temporomandibular Joint Pathology - Current Approaches and Understanding

Cytokine Authors Study groups Measuring Outcomes of study

studied technique
IL-1β Kaneyama et al. [33] Group 1: DID with ELISA Groups 1, 2 and 3 > Group 4.
clicking. (n = 8)

Group 2: DID with

locking. (n = 52)

Group 3: OA. (n = 57)

Group 4: Control. (n = 7)

Kaneyama et al. [32] Group 1: DID (n = 24) ELISA No differences among the groups.

Group 2: OA (n = 26)

Group 3: Control (n = 5)

Kaneyama et al. [35] Group 1: Control (n = 5) ELISA Groups 2, and 3 > Group 1.

Group 2: DID (n = 41)

Group 3: OA (n = 14)

Kubota et al. [36] Group 1: DID and OA ELISA Groups 1 > Group 2.

(n = 22)

Group 2: Control (n = 12) TMJs with OA > TMJs with DID.

Group 3: OA of Knee
(n = 10)

Takahashi et al. [39] Group 1: DID with ELISA IL-1β presented the higher incidence.
clicking (n = 8) Strong correlation between the presence of
IL-1β and TMJ pain in groups 1, 2, and 3.

Group 2: DID with No cytokines were detected in Group 4.

locking (n = 25)

Group 3: OA (n = 18)

Group 4: Control (n = 6)

Vernal et al. [40] Group 1: OA (n = 12) RT-qPCR Group 1 > Group 2.

Group 2: Control (n = 6)

TNF-α Kaneyama et al. [33] * ELISA Groups 1, 2 and 3 > Group 4.

Kaneyama et al. [32] * ELISA No differences among the groups.

Kaneyama et al. [35] * ELISA Groups 2, and 3 > Group 1.

TNF-α level was positively correlated

with those of IL-6, sTNFR-I and s
TNFR-II.

Takahashi et al. [39] * ELISA TNF-α presented the lower incidence.

No cytokines were detected in Group 4.

Vernal et al. [40] * RT-qPCR Group 1 > Group 2.

IL-6 Kaneyama et al. [33] * ELISA Groups 1, 2 and 3 > Group 4.

Kaneyama et al. [34] Group 1: Control (n = 7) ELISA In groups 2 and 3 was significantly higher
in joints with osseous changes in the
condyle.

Group 2: DID (n = 39) No cytokines detected in group 1.

Group 3: OA (n = 22)
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Cytokine Authors Study groups Measuring Outcomes of study

studied technique
Kubota et al. [36] * ELISA Groups 1 > Group 2.

TMJs with OA > TMJs with DID.

Takahashi et al. [39] * ELISA Group 1, 2 and 3 presented at least 1 of
the cytokines in 64.5% of the cases.
Vernal et al. [40] * RT-qPCR Group 1 > Group 2.

IL-17 Kaneyama et al. [34] * ELISA Detection rate of IL-17 was low, and
there was no association between the
concentration of IL-17 and the presence
or absence of osseous changes.
Vernal et al. [40] * RT-qPCR Group 1 > Group 2.
IL-8 Kaneyama et al. [33] * ELISA Groups 1, 2 and 3 > Group 4.
Takahashi et al. [39] * ELISA Group 1, 2 and 3 presented at least 1 of
the cytokines in 64.5% of the cases.
TGF-β1 Fang et al. [29] Group 1: DID (n = 12) ELISA Group 2 > Group 1.
Group 2: OA (n = 15)
Group 3: Control (n = 4)
IL-11 Kaneyama et al. [34] * ELISA In groups 2 and 3 was significantly higher
in joints with osseous changes in the
condyle.

RANKL Wakita et al. [42] Group 1: DID with ELISA No significance difference in RANKL
reduction (n = 25) concentration between group 4 compared
to the rest of groups.
Group 2: DID without RANKL/ OPG ratio in group 3 was
reduction (n = 39) increased.
Group 3: OA (n = 53)
Group 4: Control (n = 13)
IL-10 Fang et al. [29] * ELISA Undetectable in all the groups.
Vernal et al. [40] * RT-qPCR Group 2 > Group 1.
OPG Kaneyama et al. [32] * ELISA Group 3 > Group 2.
Wakita et al. [42] * ELISA Group 4 > Groups 1, 2, and 3.
RANKL/OPG ratio in group 3 was
increased.

Table 5. Molecular mediators proposed as associated with signs and symptoms of TMJ disorders.

turn induce the RANKL expression on synovial fibroblast and osteoblasts [92]. Recently, it
has been reported that IL-17, rather than IL-12 or IFN-γ, is critical for the onset of autoim-
mune arthritis [91, 92]. Thereby, the role of IL-17 in bone metabolism-associated diseases
has been extensively defined, and this role is mainly associated with the induction of proin-
flammatory cytokines, chemokines, and matrix metalloproteinases that leads pathological
bone and/or cartilage damage [89, 93, 94].
86 Temporomandibular Joint Pathology - Current Approaches and Understanding

Our recent data revealed that higher levels of IL-1β, IL-17, and IL-22, associated with the
Th1, Th17, and Th22-pattern of immuno-inflammatory response, were detected in TMJ-OA
as compared with DDWR.  Increased cytokine levels significantly correlated with an
enhancement of RANKL expression and the detection of imagenological signs of articular
bone degeneration [95]. IL-22 plays a proinflammatory role through the synergistic activ-
ity with IL-1β and TNF-α [96–98] and IL-22 can indirectly induce osteoclastogenesis and
bone resorption by the induction of Th17 lymphocyte activity and IL-17 production [99]. In
fact, previous reports have detected over-expressed levels of IL-22 in rheumatoid arthritis
synovial fibroblasts, demonstrating a pathogenic role of IL-22 in the rheumatic joint inflam-
mation and destruction through the modulation of the IL-1β and IL-17R expression [100,
101]. In general terms, we believe that the Th1/Th17/Th22 immuno-inflammatory cell path-
ways, associated with the production of IL-1β, IL-17, and IL-22, play a central role in the
pathogenesis of the TMJ-OA. Similarly, the role of the Th2/Th9/T regulatory cell pathways,
responsible for the production of IL-4, IL-9, and TGF-β1, respectively, could be associated
with TMJ-OA disease healing.

7. Therapeutic potential of T regulatory lymphocytes in TMJ-OA

At the beginning of 1980s, the existence of a suppressor T cell population was proposed, sug-
gesting that these T cells restrict the induction or expression of effector T cells and thereby
prevent and control exaggerated immune response and autoimmune disease development
[102]. The modern view of suppressor cells began with the observation that the transfer of
T cells depleted of the IL-2Rα+ (CD25+) cell subpopulation induced multiorgan autoim-
munity in recipient mice [103]. Nowadays, suppressor T cells have been renamed and are
currently known as T regulatory cells (Tregs). These cells have been isolated from mice
and humans and their regulatory functions have been demonstrated not only in vitro but
also in vivo. It has also been established that several types of cells carry out regulatory
activities. These include IL-10-secreting CD4+ T regulatory-1 (Tr1) cells, TGF-β1-secreting
CD4+ Th3 cells, NKT cells, CD8+CD28−Foxp3+ cells, γ/δ TCR cells, and CD4+CD25highFoxp3+
T cells, the last one widely accepted as “professional Tregs” or naturally occurring Tregs
[104, 105].

Natural Tregs are CD4+ T cells that develop and mature in the thymus carry out their
regulatory function during normal surveillance of self-antigens [106]. On normal individu-
als, they represent 5–10% of the peripheral CD4+ T cell population and are characterized
by the constitutive expression of high levels of CD25 and low levels of CD45RB [107]. In
turn, adaptive Tregs represent CD4+ T cells that acquire their regulatory activity during
activation [106]. Unlike natural Tregs, which came out from the thymus as CD4+CD25+
cells, adaptive Tregs originate from peripheral naïve T cells [106]. They are derived from
CD4+CD25− T cells and show variable expression of CD25 during their mature phenotype,
depending on the disease and the site of regulatory activity [108] Induced Tregs require
TCR stimulation for induction of regulatory functions and have demonstrated limited pro-
liferation in vitro [109].
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Although induced Tregs and effector Th17 cells play different roles during the immunity,
reciprocal developmental pathways have been demonstrated for their generation. Naïve T
cells exposed to TGF-β1 up-regulate Foxp3 and become induced Tregs; however, when cul-
tured with TGF-β1 and IL-6, naïve T cells generate IL-17 secreting Th17 cells with patho-
logic activities [110, 111]. Thus, when the immune response is not activated, TGF- β1
favors the generation of induced Tregs, which suppress inflammation; however, when the
inflammatory process is established, IL-6 is synthesized during the innate immune response,
inhibiting the generation of Tregs and inducing the differentiation of proinflammatory of
Th17 cells in presence of TGF-β1 [112]. Thus, induced Tregs and Th17 lymphocytes may arise
from the same precursor cell and selective differentiation would depend on the local cytokine
milieu, which would determine the predominance of either Tregs with suppressor activity or
Th17 cells with pathologic activities, determining the outcome of the disease [112].

8. Conclusion

The therapeutic potential of Tregs has created a lot of expectations and a large number of
publications have assayed their properties either in vitro or in experimental models. Tregs
suppress in vitro proliferation and cytokine production from co-cultured effector T cells
[113]. Tregs suppressed autoimmune diabetes and altered the course of lupus in a TGF-β1-
dependent manner [114]. Additionally, induced Tregs have been successfully used to prevent
organ graft rejection [115]. A model of Treg therapy aimed to induce tolerance and restora-
tion of function might show promising results during treatment of TMJ-OA, but additional
research is necessary for a better understanding of Treg physiology and to solve several yet
unanswered aspects associated to their therapeutic potential in humans.

Author details

Gustavo Monasterio1, Francisca Castillo1, Daniel Betancur2, Arnoldo Hernández3,

Guillermo Flores4, Walter Díaz4, Marcela Hernández1,5 and Rolando Vernal1,6*

*Address all correspondence to: [email protected]

1 Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Chile

2 Molecular Immunology Laboratory, Faculty of Biological Sciences, Universidad de

Concepción, Chile

3 Anatomy and Biology Program, Faculty of Medicine, Universidad de Chile, Chile

4 Department of Prosthesis, Faculty of Dentistry, Universidad de Chile, Chile

5 Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile,

Chile

6 Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Chile

88 Temporomandibular Joint Pathology - Current Approaches and Understanding

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