Int. J. Morphol.

,
35(3):870-876, 2017.

Role of Hyaluronic Acid in the Homeostasis and

Therapeutics of Temporomandibular Joint Osteoarthritis

Rol del Ácido Hialurónico en la Homeostasis y Terapéutica

de la Osteoartritis de Articulación Temporomandibular

Veronica Iturriaga1,2,3; Bélgica Vásquez4; Carlos Manterola5,6 & Mariano del Sol5

ITURRIAGA, V.; VÁSQUEZ, B.; MANTEROLA, C. & DEL SOL, M. Role of hyaluronic acid in the homeostasis and therapeutics
of temporomandibular joint osteoarthritis. Int. J. Morphol., 35(3):870-876, 2017.

SUMMARY: The aim of this study was to perform a literature review regarding the role of hyaluronic acid (HA) in the homeostasis
and therapeutics of temporomandibular joint (TMJ) osteoarthritis (OA). The TMJ has characteristics that give it special adaptation and
recovery abilities, where HA plays a fundamental role in helping to maintain joint homeostasis, which is affected in pathological processes
like OA. OA is a chronic degenerative multi-factor disease that can affect all the components of the synovial joints, causing degradation
of the articular cartilage, extracellular matrix and breakage in the HA molecules. HA is a non-branched linear polysaccharide with
viscosupplementation, anti-inflammatory, lubrication and pain relief effects; it also activates the intrinsic repair processes of the cartilage
and normalizes the endogenous production of HA by the synoviocytes. In recent years, the therapeutic use of HA has shown evidence
that supports its application in TMJ OA, improving viscosupplementation capacity, acting at the cellular and molecular levels, reducing
various inflammatory mediators and improving the reparative characteristics. Its use has been studied in animal models and in humans.
However, no consensus has been reached in terms of concentrations, dose, application frequency or molecular weight to be used.

KEY WORDS: Hyaluronic acid; Osteoarthritis; Temporomandibular joint; Temporomandibular disorders;

Viscosupplementation.

INTRODUCTION

The temporomandibular joint (TMJ) is classified as It has been suggested that HA presents properties that
a synovial joint, condylar, ellipsoid or bicondylar, and could maintain the internal homeostasis of the TMJ, helping
presents two main axes of movement, making it one of the it to adapt to different pathologies, producing the
most complex joints in the body (Vasconcellos et al., 2007). viscosupplementation phenomenon. Currently exogenous
HA (EHA) is being used as an alternative therapy, and there
Among the diseases that can affect the TMJ are is evidence that would support its use in TMJ OA.
inflammatory-degenerative disorders like osteoarthritis
(OA), which is one of the most significant pathologies The aim of this study was to perform a literature
affecting this joint, and is known as temporomandibular joint review regarding the role of HA in the homeostasis and
disorder (TMD) (Manfredini et al., 2010; Güler et al., 2011). treatment of TMJ OA.
OA is a chronic degenerative multi-factor disease that can
affect all components of the synovial joints (Kim et al., 2001; Characteristics of the temporomandibular joint. The
Uchôa de Rezende & Constantino de Campos, 2012), where human TMJ is composed of the condylar process of the
hyaluronic acid (HA) plays an important role in the disease mandible, the mandibular fossa and the articular tubercle of
adaptation process. the squamous part of the temporal bone (Vasconcellos et

1
Departamento de Odontología Integral del Adulto, Universidad de La Frontera, Temuco, Chile.
2
Programa Doctorado en Ciencias Médicas, Universidad de La Frontera, Temuco, Chile.
3
Becario CONICYT, PFCHA/ Doctorado Nacional/2015-21151352.
4
Facultad de Ciencias de la Salud. Universidad de Tarapacá. Arica, Chile.
5
Centro de Estudios Morfológicos y Quirúrgicos (CEMyQ), Universidad de La Frontera, Temuco, Chile.
6
Departamento de Cirugía, Universidad de La Frontera, Temuco, Chile.
Funding: This research was financed by CONICYT through national doctoral scholarships. CONICYT, PFCHA/ Doctorado Nacional/ 2015-21151352.

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 ITURRIAGA, V.; VÁSQUEZ, B.; MANTEROLA, C. & DEL SOL, M. Role of hyaluronic acid in the homeostasis and therapeutics of temporomandibular joint osteoarthritis.
Int. J. Morphol., 35(3):870-876, 2017.

al.). The two bones are separated by a concave-convex arti- hand, Oyanguren et al. (2010), studied the amount and
cular disk formed by fibrous and dense connective tissue with distribution of collagen and elastic fibers, finding a
intertwined bundles of collagen devoid of blood vessels or relationship with the functional role of joint tissues where
nerve fibers at its core (Vasconcellos et al.; Okeson, 2008). they are found.
The joint capsule has a synovial inner layer, which is
responsible for the secretion of synovial fluid (SF), contributing Temporomandibular joint osteoarthritis. TMJ OA is a
to the lubrication of the TMJ (Vasconcellos et al.). slow, progressive and debilitating heterogeneous condition
that can cause pathological changes on the joint surfaces
Covering the bone tissue of the condyle and (Kim et al.; Uchôa de Rezende & Constantino de Cam-
mandibular fossa on the joint surface, there is a 2 mm-thick pos). Clinically, it is characterized as presenting joint pain,
layer of dense fibrous tissue that serves to absorb pressures a reduced range of mandibular movement, a crackling
and distribute them across the surface (Wurgaft & noise and functional difficulty (Okeson). In terms of
Montenegro, 2003). This joint surface has four different imaging, OA can be detected through tomographies like
histological areas that give the TMJ distinctive properties computed tomography or cone beam computed
(Hansson et al., 1977). The surface layer, called the joint or tomography and magnetic resonance (López López et al.,
fibrous area, is formed by fibroblasts and has dense fibrous 2005). Imaging features to be found include erosion,
connective tissue with fibers strongly bound to support the sclerosis, the presence of osteophytes and flattening of the
forces of movement. Contrary to what occurs in most surfaces (Güler et al.).
synovial joints, which are covered by hyaline cartilage,
creating an advantage in terms of repair, sensitivity to aging Histopathological characteristics include a
and support for the forces of movement (Wurgaft & progressive degeneration of the articular cartilage (Cledes
Montenegro; Okeson). The second layer, called proliferative et al., 2006), fibrillation and erosion of the articular surfaces,
or cellular, is very thin and is located mainly in the lateral proliferation of chondrocytes, eburnation of the articular
areas of the condylar surface, near the synovial capsule and cartilage, synovitis, changes and exposure in the subchondral
membrane. It is composed of undifferentiated mesenchymal bone and formation of osteophytes at the articular margin
tissue giving the articular cartilage the chance to proliferate, (Cledes et al.; Güler et al.). The imbalance occurs between
allowing the TMJ to respond to functional demands and the process of synthesis and degradation within the
loads. In cases of prolonged mandibular immobilization, it chondrocytes, which leads to the loss of cartilaginous tissue.
has been noted that this layer can be lost, making joint tissue As a result, over time a degenerative process of the joint
neoformation and recovery impossible (Wurgaft & surfaces occurs, characterized by degradation of the
Montenegro). The authors cited, report that the third fibro cartilaginous matrix and synthesis inhibition of its
cartilaginous layer is formed by a cartilaginous matrix, components, leading to joint deterioration and pain in
chondrocytes in its lagoons and type I collagen fibers, some advanced stages (Güler et al.). It has been suggested that
intertwined, others radially, providing increased resistance this inflammatory reaction could contribute to the
to lateral and compression forces. The thickness of this layer development and progression of the pathology (Hirota,
varies depending on its position, it is thicker in areas 1998).
subjected to greater pressure, and thinner in areas further
from the working space. Finally, the fourth calcified layer is High levels of inflammatory mediators in the SF of
the deepest and is formed by chondroblasts, chondrocytes patients with TMD have been detected, such as disk
and osteoblasts distributed throughout the articular cartilage. displacement and OA (Quinn & Bazar, 1990; Shafer et al.,
In this layer, the chondrocytes give rise to the osteoblasts 1994; Fu et al., 1995). Among the most recognized
from inside the bone and are the ones charged with inflammatory mediators are arachidonic acid derivatives,
synthesizing the collagen, proteoglycans, glucoproteins and related enzymes and some cytokines (Uchôa de Rezende &
enzymes that form the extracellular matrix. This is how a Constantino de Campos). Cytokines like interleukin-1b (IL-
mesh of collagen, proteoglycans and HA is formed which 1b) and tumor necrosis factor a (TNF-a) can affect bone
attracts water and aids in supporting joint loads, keeping the resorption, the proliferation of SF and cause the destruction
internal and external joint pressures in balance (Wurgaft & of the cartilage (Hirota). These cytokines are derived from
Montenegro; Okeson). monocytes, synovial fibroblasts and epithelial cells, which
can stimulate the production of arachidonic acid metabolites
In some pathologies, such as condylar hyperplasia, a like some prostaglandins (Hirota), directly and indirectly
variation has been noted in the size and definition of these increasing joint damage, producing a vicious circle where
layers, in addition to differences in the type of collagen fibers disintegration of the cartilage occurs due to changes in the
and cellularity involved (Vásquez et al., 2016). On the other HA of the SF (Xinmin & Jian, 2005).
871
 ITURRIAGA, V.; VÁSQUEZ, B.; MANTEROLA, C. & DEL SOL, M. Role of hyaluronic acid in the homeostasis and therapeutics of temporomandibular joint osteoarthritis.
Int. J. Morphol., 35(3):870-876, 2017.

Additionally, a decomposition of the HA is produced, Under in vitro conditions, HA presents a variety of

reducing its concentration and molecular weight in the joint, effects on cell and joint damage (Brandt et al.). These include
which in turn produces a change in the nature of the SF inhibition of prostaglandin E2, synthesis of inerleukin-1
(Balazs et al., 1967; Dahl et al., 1985). Viscosity and (Yasui et al., 1992; Tobetto et al., 1992), and protection
molecular barrier functions are also weakened, preventing against the disintegration of proteoglycans and cytotoxity
protection of the articular proteoglycan matrix, making it induced by oxygen free radicals. In addition, it affects
difficult to inhibit the inflammatory process (Goldberg et leukocyte adhesion, proliferation, migration and
al., 1991; Xinmin & Jian). It has been suggested that HA phagocytosis (Ghosh et al., 1995); it directly influences the
modifies the flow of the SF through the joint. Although, it control mechanism of monocyte activation; in the cartilage
has been reported that the flow of SF is reduced in OA, most it has been seen to suppress degradation of the cartilaginous
of the measurements indicate that there is a faster elimination matrix by fibronectin fragments (Homandberg et al., 1997;
of HA and proteins in the joints with synovitis than in joints Williams et al., 1997; Brandt et al.).
with OA (Brandt et al., 2000).
Animal studies have shown that EHA infiltration has
Hyaluronic acid and its role in joint homeostasis. HA is a positive effects on joint pain reduction and OA (Armstrong,
non-branched linear polysaccharide comprised of several 1994; Sakakibara et al., 1994; Gosh et al.; Neo et al., 1997;
units of glucuronic acid disaccharides and N- Shimizu et al., 1998). Although its mean life is 13 to 30
acetylglucosamine (Brandt et al.; Kim et al.). It is synthesized hours, the intra-articular application yields persistent benefits
by synoviocytes, fibroblasts and chondrocytes present in the (Bertolami et al., 1993; Sato et al., 2001; Uchôa de Rezende
connective tissue of all mammals (Brandt et al.). In addition, & Constantino de Campos), and increases the molecular
it is the largest natural component of SF and an important weight and amount of HA synthesized by the synovia (Brandt
component of the articular cartilage (Xinmin & Jian). et al.; Uchôa de Rezende & Constantino de Campos). It is
proposed that the positive effects are due to direct and indirect
In physiological conditions, HA plays an important consequences of viscosupplementation (Uchôa de Rezende
role in maintaining intra-articular homeostasis (Manfredini & Constantino de Campos), as this compensates for the
et al., 2010). Its action stems from the ability of the viscosity of the SF that has decreased as a result of OA
polysaccharides to connect to each other when they are in (Xinmin & Jian); therefore, EHA infiltration could improve
solution, forming a network that provides a high degree of the rheological properties of the HA, modulate the joint
viscosity to the SF (Brandt et al.; Xinmin & Jian), thereby inflammation, promote a better distribution of forces,
obtaining a “cushioning” effect in the support of loads. In stabilize the extracellular matrix, stimulate the proliferation
addition, it has anti-inflammatory and lubricant effects, re- of chondrocytes, regulate the production/degradation of type
lieves pain, activates intrinsic repair processes of the cartilage II collagen and avoid sensitization of pain receptors in joints
and normalizes the endogenous production of HA by the with OA (Kim et al.; Uchôa de Rezende & Constantino de
synoviocytes (Manfredini et al., 2010). Its metabolic activity Campos). In addition, it would reduce the gene expression
also facilitates the nutrition of the joint disk and cartilage in of cytokines and enzymes associated with OA, and would
vascular areas (Coronado et al., 2015). cause the decrease in prostaglandins and concentration of
metalloproteinases (Uchôa de Rezende & Constantino de
In situations where rapid mandibular movements Campos).
occur, elasticity is the main property that SF possesses, but
in slow mandibular movements viscosity becomes the main With respect to the origin of EHA preparations, they
characteristic (Xinmin & Jian). This is important because can be of avian or non-avian origin (Uchôa de Rezende &
viscosity helps joint lubrication and occurs often with HA. Constantino de Campos; Brandt et al.). In the first case, they
are derived from rooster comb and in the second from bac-
Hyaluronic acid as a therapeutic alternative. In recent teria like Streptococcus zooepidermicus. The latter pose the
years, intra-articular infiltration of EHA has been gaining least potential of an allergen (Uchôa de Rezende &
ground in the treatment of TMJ OA as a Constantino de Campos). Examples of preparations of avian
viscosupplementation method (Manfredini et al., 2010). origin would be Synvisc® or Synvisc®oneTM, and of non-
From the biochemical point of view, this molecule is a drug avian origin Suprahyal®.
in the glycosaminoglycan group. However, in physiological
conditions it is found in the form of salt, as sodium Application of EHA: Studies on humans. Manfredini et
hyaluronate or hyaluronan; its properties can vary in relation al. (2010) conducted a systematic review, finding seven
to its molecular weight and shape (Uchôa de Rezende & publications where EHA was used in the treatment of patients
Constantino de Campos). with TMJ OA. In these publications, all reported a marked
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 ITURRIAGA, V.; VÁSQUEZ, B.; MANTEROLA, C. & DEL SOL, M. Role of hyaluronic acid in the homeostasis and therapeutics of temporomandibular joint osteoarthritis.
Int. J. Morphol., 35(3):870-876, 2017.

improvement in the measured variables (ranges of movement molecular weight than human HA. However, they can be
and pain). After application of EHA in patients with TMD, divided into: EHA of low molecular weight, 0.5-1 x 106 Da,
there was a significant reduction in inflammatory cytokines such as Hyalgan® or Suprahyal®; EHA of intermediate
like IL-1β and TNF-α (Hirota), avoiding progression of the molecular weight, 1.8 x 106 Da, Viscoseal®; and EHA of
pathology. Iturriaga et al. (2017) performed a systematic high molecular weight, 6 x 106 Da, Synvisc ® or
review in which the effect of the EHA was assessed in the Synvisc®oneTM (Balazs & Denlinger, 1993).
regulation of inflammatory mediators in TMJ OA in humans,
finding that its effect also extends to the plasminogen Guarda-Nardini et al. (2012) compared the effects
activation system and to nitric oxide. The authors indicated of EHA of low and intermediate molecular weight in TMJ
that HA not only acts as a viscosupplement, mechanically OA in humans, finding no statistically significant differences:
reducing the friction, but can also play a role as an Both were beneficial with respect to different symptoms.
inflammatory mediator in the osteoarthritic process by On the other hand, a study conducted on humans compared
regulating the proteolytic activation of the plasminogen six TMJ infiltration protocols prior to arthrocentesis with
activation, avoiding the release of proinflammatory different infiltration rates and molecular weight. Pain when
mediators, reducing the activation of metalloproteinase chewing, mouth opening and joint noise were compared,
proforms and modulating neurotransmission and and no statistically significant differences were found
vasodilatation processes. between the groups. However, the protocol of a weekly
infiltration of EHA of low molecular weight for five weeks
Manfredini et al. (2010) found that the application showed slightly better results than the rest, suggesting further
of a single infiltration of EHA showed better results than study is required (Manfredini et al., 2012).
the use of metacarbamol plus paracetamol (Oliveras-More-
no et al., 2008; Manfredini et al., 2010). Positive effects In relation to the physicochemical effects of EHA, it
were also found in comparison with patients without is suggested that the higher the molecular weight the more
treatment (Bjørnland et al., 2007; Møystad et al., 2008); and positive the effect; however, some authors hypothesize that
no differences were found with the short-term use of intra- excessive molecular size (between 1-6 x 106 Da) would
articular corticosteroids (Guarda-Nardini et al., 2005; prevent the HA from moving from the intra-articular
Manfredini et al., 2010). However, the use of corticosteroids environment to the intercellular environment in such a way
can present some adverse effects such as progression of the that it would not be able to act on synoviocytes and
disease and condylar resorption (Wenneberg et al., 1991; chondrocytes, which is why products with a molecular
El-Hakim et al., 2005), whereas the application of EHA does weight between 0.5-1 x 106 would be the most effective
not show any major adverse effects (Li et al., 2012; (Uchôa de Rezende & Constantino de Campos). Manfredini
Grossmann et al., 2013). According to Uchôa de Rezende et al. (2012), reported severe pain with the infiltration of
& Constantino de Campos, the minimum adverse effects EHA of high molecular weight, despite other in vivo results
described were related to the infiltration procedure, such as indicating a direct relation between molecular weight and
effusion, joint pain, burning and joint erythema, which are analgesia (Uchôa de Rezende & Constantino de Campos).
all temporary.
Application of EHA: Studies on animals. On the other
There is no consensus in the literature regarding the hand, in vivo studies on animals are frequently used to study
concentrations, dosage and application frequency of EHA in pathological mechanisms and the development of new
humans. The most frequently used concentrations are 1 %, therapies in TMJ AO. A review by Coronado et al. found
0.5 % and 1.5 %, with the first being the most frequent (Coro- four studies on the topic, which used different animal species,
nado et al.). In terms of dosage, applications of 0.5 ml, 0.7 ml, such as rabbits, rats and sheep. In general, the species used
1 ml and 2.6 ml can be found, and with respect to the depends on the aim of the study. Rats are linked mainly to
frequency, the most frequently used protocols are single the study of the nervous system and nociception, rabbits to
infiltration or, weekly infiltration for five weeks, which have TMD models such as disk or inflammatory disorders, and
been extrapolated mainly from knee procedures. In the case sheep to surgical procedures (Herring, 2003).
of the knee joint, the only medication that has shown benefits
with a single infiltration is Synvisc®oneTM, unlike the other As mentioned, the rabbit presents some advantages
hyaluronates, which must be infiltrated once a week for 3-5 when studying inflammatory disorders of the TMJ. The
weeks (Uchôa de Rezende & Constantino de Campos). rabbit has similarities with the characteristics of the human
TMJ in terms of its anatomy and movements, mainly the
Few studies describe molecular weight. Generally, it laterality that gives it a mobility not found in other animals
may be said that most of the preparations present a higher (Savalle et al., 1990; Güler et al.). In addition, it is a
873
 ITURRIAGA, V.; VÁSQUEZ, B.; MANTEROLA, C. & DEL SOL, M. Role of hyaluronic acid in the homeostasis and therapeutics of temporomandibular joint osteoarthritis.
Int. J. Morphol., 35(3):870-876, 2017.

manageable animal like the rat, but unlike the rat, the rabbit CONCLUSION
has a high rate of bone and joint turnover, which makes it
possible to observe joint physiological and pathological
processes more quickly, this being an advantage when The TMJ is one of the most complex joints in the body,
studying inflammatory disorders of the TMJ. Likewise, it is presenting unique features that afford it great adaptive and
preferable for the subjects to be male to avoid a hormonal reparative capacity. TMJ OA is a frequent pathology that pro-
influence on the metabolism of the articular cartilage and duces an imbalance in joint homeostasis, causing degradation
bone (Güler et al.). of the cartilage and extracellular matrix, inhibition of the
synthesis of the joint components, an increase in inflammatory
In summary, Coronado et al., mentioned that the mediators in the SF and breakage in the hyaluronic acid
most reported application frequencies in animal models, molecules, thereby reducing their concentration and molecular
are the single doses of EHA and a weekly dose for five weight. The use of EHA has provided evidence that supports
consecutive weeks. In relation to the concentration, the its application in TMJ OA; however, there is insufficient
most used was EHA at 1 %; however, the doses vary among evidence comparing different application protocols in humans
species. According to the authors, in rabbits the and animal models, which encourages further research into
concentrations can fluctuate between 0.1 ml and 0.5 ml, its advantages and applications.
0.12 ml in rats and 1 ml in sheep. The molecular weight of
the EHA was not reported in any of the studies reviewed ITURRIAGA, V.; VÁSQUEZ, B.; MANTEROLA, C. & DEL
(Coronado et al.). Based on what was previously indicated SOL, M. Rol del ácido hialurónico en la homeostasis y terapéutica
in animal models, there is also no consensus regarding the de la osteoartritis de articulación temporomandibular. Int. J.
different EHA infiltration protocols, since to date no Morphol., 25(3):870-876, 2017.
comparison has been made among them. Table I shows a
summary of the physiological and therapeutic properties RESUMEN: El objetivo de este estudio fue realizar una
of hyaluronic acid. revisión de la literatura respecto del rol del ácido hialurónico (AH)
en la homeostasis y terapéutica de la osteoartritis (OA)
de la articulación temporomandibular (ATM). La
ATM presenta características que le confieren pro-
Table I. Physiological and therapeutic role of hyaluronic acid in the piedades de adaptación y recuperación especiales,
temporomandibular joint. donde el AH juega un rol fundamental ayudando a
Physiological role of hyaluronic acid mantener la homeostasis articular, la cual se ve afec-
tada en procesos patológicos como la OA. La OA es
Provides a high degree of viscosity to the sinovial fluid. una enfermedad multifactorial crónica degenerativa
Has anti-inflammatory effects. que puede afectar a todos los componentes de las ar-
ticulaciones sinoviales, generando degradación del
Increases joint lubrication. cartílago articular, matriz extracelular y quiebre de
Contributes to pain relief in pathological processes. las moléculas de AH. El AH es un polisacárido lineal
no ramificado que presenta efectos de
Activates intrinsic cartilage repair processes.
viscosuplementación, antiinflamatorios, lubricantes,
Stimulates endogenous production of hyaluronic acid. en el alivio del dolor, permite además, activar proce-
Facilitates the nutrition of the disc and articular cartilage. sos intrínsecos de reparación del cartílago y normali-
zar la producción endógena de AH por parte de los
Therapeutic role of hyaluronic acid sinoviositos. En los últimos años el uso terapéutico
del AH ha presentado evidencia que sustenta su apli-
Offers visco-supplementation to the joint. cación en OA de ATM mejorando la capacidad de
viscosuplementación, actuando a nivel celular y
Inhibits PGE2, IL-1, TNF-α and metalloproteinases. molecular, disminuyendo diversos mediadores
Decrease the cytotoxicity given by oxygen free radicals. inflamatorios y mejorando las características
reparativas. Su uso se ha estudiado en modelos ani-
Decreases the degradation of proteoglycans. males y en humanos, sin embargo no existe consenso
Affect the adherence, proliferation, migration and leukocyte phagocytosis. en cuanto a concentraciones, dosis, frecuencias de
aplicación y peso molecular a utilizar.
Prevents sensitization of joint pain receptors.
Increases the molecular weight and amount of endogenous hyaluronic acid. PALABRAS CLAVE: Acido hialurónico;
Osteoartritis; Articulación temporomandibular;
Improves rheological properties of endogenous hyaluronic acid.
Trastornos temporomandibulares; Viscosuple-
mentación.

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 ITURRIAGA, V.; VÁSQUEZ, B.; MANTEROLA, C. & DEL SOL, M. Role of hyaluronic acid in the homeostasis and therapeutics of temporomandibular joint osteoarthritis.
Int. J. Morphol., 35(3):870-876, 2017.

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