Connective Tissue Research

ISSN: 0300-8207 (Print) 1607-8438 (Online) Journal homepage: http://www.tandfonline.com/loi/icts20

Recent advances in the understanding of

molecular mechanisms of cartilage degeneration,
synovitis and subchondral bone changes in
osteoarthritis

Yingliang Wei & Lunhao Bai

To cite this article: Yingliang Wei & Lunhao Bai (2016) Recent advances in the understanding
of molecular mechanisms of cartilage degeneration, synovitis and subchondral
bone changes in osteoarthritis, Connective Tissue Research, 57:4, 245-261, DOI:
10.1080/03008207.2016.1177036

To link to this article: http://dx.doi.org/10.1080/03008207.2016.1177036

Published online: 10 Jun 2016.

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CONNECTIVE TISSUE RESEARCH
2016, VOL. 57, NO. 4, 245–261
http://dx.doi.org/10.1080/03008207.2016.1177036

REVIEW

Recent advances in the understanding of molecular mechanisms of cartilage

degeneration, synovitis and subchondral bone changes in osteoarthritis
Yingliang Wei and Lunhao Bai
Department of Orthopedic Surgery, Sheng–Jing Hospital, China Medical University, ShenYang, China

ABSTRACT ARTICLE HISTORY

Osteoarthritis (OA), the most common form of degenerative joint disease, is linked to high Received 26 October 2015
morbidity. It is predicted to be the single greatest cause of disability in the general population Revised 22 March 2016
by 2030. The development of disease-modifying therapy for OA currently face great obstacle Accepted 5 April 2016
Published online 9 June 2016
mainly because the onset and development of the disease involve complex molecular mechan-
isms. In this review, we will comprehensively summarize biological and pathological mechanisms KEYWORDS
of three key aspects: degeneration of articular cartilage, synovial immunopathogenesis, and Cartilage degeneration;
changes in subchondral bone. For each tissue, we will focus on the molecular receptors, cytokines, inflammation; molecular
peptidases, related cell, and signal pathways. Agents that specifically block mechanisms involved mechanisms; osteoarthritis;
in synovial inflammation, degeneration of articular cartilage, and subchondral bone remodeling subchondral bone
can potentially be exploited to produce targeted therapy for OA. Such new comprehensive agents
will benefit affected patients and bring exciting new hope for the treatment of OA.

Introduction calcified cartilage zone (6). The chondrocytes are

embedded in a matrix consisting of a network of col-
Osteoarthritis (OA), the most common form of degen-
lagen fibers (primarily type II) as well as varying
erative joint disease, is a major health burden as it is the
amounts of proteoglycans. The chondrocytes produce
most common form of arthritis and is linked to high
and maintain the physical function of cartilage by
morbidity. It is also predicted to be the single greatest
synthesizing and degrading matrix components in
cause of disability in the general population by 2030 (1),
response to environmental changes such as changes in
with an estimated 35% of people eventually suffering from
growth factors, cytokines, and biomechanical forces
OA. Disease rate is likely to increase year by year con-
(7,8). Once the microenvironment changes, the altera-
tinuously as the global population ages and working lives
tion in the normal physiologic balance under the influ-
become longer in developed countries (2). Despite its high
ence of all kinds of factors lead to functional
prevalence and substantial public health impact, disease
abnormality of these cells. However, the precise mole-
etiology remains incompletely understood. While several
cular mechanism initiating chondrocyte malfunction-
risk factors have been associated with OA, including
ing remains unknown. In this review, we discuss recent
genetic predisposition, aging, obesity, and joint malalign-
molecular mechanisms involved in the development of
ment (3,4), OA is not a simple process of wear and tear
OA. Our review will focus on receptor ligands such as
but represents an abnormal remodeling process resulting
transforming growth factor (TGF)-β1, wingless-type
in failure of the entire joint (5). At present, molecular
(Wnt), and Indian hedgehog (Ihh); signaling molecules
mechanisms of degeneration of articular cartilage, syno-
such as β-catenin and hypoxia-inducible factor (HIF)-
vial immunopathogenesis, and changes in subchondral
2α; and peptidases such as matrix metalloproteinase
bone are well accepted to be involved in the complex
(MMP) 13 and A Disintegrin and Metalloproteinase
initiation and progression of the disease.
with Thrombospondin Motifs (ADAMTS)-4/5.
As a unique component of the joints, articular car-
In the past, OA was regarded as a non-inflammatory
tilage has received much of the attention in OA studies
form of arthritis, but the truth is that synovitis is linked
because its damage is usually the most obvious patho-
to the increased cartilage damage (9). Recent studies
logic feature prior to joint dysfunction. The tissue
suggest that a large number of OA patients experience
structure can be divided into four zones: the superficial
pain consequent to synovitis (10), plus immune factor
zone, the transitional zone, the radial zone, and the

CONTACT Lunhao Bai bailh@sj-hopital.org Department of Orthopaedic Surgery, Sheng Jing-Hospital, China Medical University, SanHao Street #36,
HePing District, ShenYang, China. Tel: 18940251711.
© 2016 Taylor & Francis
246 Y. WEI AND L. BAI
(infiltrating macrophage, immunoglobulin, and
immune complex) detection in the synovial tissue of
OA patient (7,11,12). Synovial inflammation may
therefore be associated with OA. This review will
focus on the impact of synovial inflammation on OA.
We will discuss recent developments in (I) the correla-
tion between synovitis and OA, (II) innate immunity
and the development of synovial inflammation (syno-
vitis) (including cellular factors, the complement sys-
tem, chemokines and cytokines), and (III) the role of
meniscus, metabolic inflammation and nuclear factor
(NF)-κB in OA.
Growing evidence suggests that OA is an organ-
level failure involving not only the cartilage surface
but also adjacent organizational structures. Changes
in the subchondral bone can explain clinical symp-
toms such as osteophyte formation. The importance
of subchondral bone remodeling has been empha-
sized not only in humans but also in animal models
of acquired OA (13). Studies suggest that various
factors released from the subchondral bone environ-
ment are able to regulate cartilage metabolism (6,13)
and could therefore become critical therapeutic tar-
get to control the disease, improving both clinical
symptoms and joint structural erosion. This review
will summarize the current knowledge on the role of
subchondral bone remodeling in the development of
OA through the induction of an abnormal pheno-
type in osteoblasts of subchondral bone and the
effects of chondrocytes on subchondral bone.
Degenerative change of articular chondrocytes
in OA
In recent times, there has been an explosion of reports
describing abnormalities in the gross appearance, mate-
rial properties, biochemical composition, cellular
morphologies, and gene expression of articular carti-
lages from human to animal models with OA-like
joints (14–16). These recent, detailed findings related
to the molecular mechanisms of OA development will
be summarized below (Figure 1b).
Effect of TGF-β in articular chondrocyte
degeneration in OA
Intracellular chondrocyte signaling is initiated by TGF-
β, through the combined TGF-β type I and II trans-
membrane Ser/Thr kinase receptors (17). TGF-β first
binds to the type II receptor, triggering recruitment of
the type I receptor. This active type II receptor has the
ability to phosphorylate the GS domain of the type I
receptor (18). Gradually the accumulated activated type
I receptor can phosphorylate R-Smads at the
C-terminus of Smad2/3 (19). The phosphorylated
Smad2/3 then dissociates from the receptor complex
and forms a heteromeric complex called Smad4,
which translocates into the nucleus and associates
with other DNA-binding proteins to regulate gene tran-
scription (20,21). The growth factor TGF-β, which
strongly inhibits articular chondrocyte hypertrophy
and maturation, also represents a potential mechanism
in the development of OA.
Mice with the Smad3 gene knockout show chondro-
cyte hypertrophy at an early stage, followed by
decreased proteoglycan production, articular surface
fibrillation, and, in the late stage, chondrocyte cluster-
ing in the deeper zone of articular cartilage, changes
similar to those observed in human OA (21–23).
Smurf2 is an inhibitor of TGF-β signaling in articular
chondrocytes and acts to promote chondrocyte hyper-
trophy. Smurf2 is highly expressed in human OA car-
tilage but is not present in normal cartilage. TGF-β
signaling is decreased, and expression of chondrocyte
hypertrophic markers (ColX and MMP13) is increased
in transgenic mice (24), leading to progressive articular
cartilage degradation, including reduced cartilage area
and fibrillation, as well as subchondral sclerosis and
osteophyte formation (25). These findings suggest that
loss of TGF-β signaling represents one of the possible
mechanisms underlying OA development.
Effect of the Wnt/ß-catenin signaling pathway on
articular chondrocyte degeneration in OA
As a key molecule in the canonical Wnt signaling
pathway, β-catenin controls multiple critical pro-
cesses acting on the progression of OA (26). Wnt
signaling can also promote cartilage degradation by
activation of catabolic genes like MMPs in chondro-
cytes (27). Cytokine IL-1 was known as an activator
of the WNT pathway involved in cartilage destruc-
tion during OA (28), When Wnt (especially Wnt5
and Wnt7) binds to its receptor Frizzled and the co-
receptors lipoprotein receptor-related protein (LRP)
5/6, the activity of the downstream signaling proteins
Dishevelled (Dsh) and Axins 1 and 2 are altered. This
leads to the inactivation of Ser/Thr kinase glycogen
synthase kinase (GSK)-3β, thus inhibiting the ubiqui-
tination and degradation of β-catenin triggered by
GSK-3β. β-catenin then accumulates in the cytoplasm
and translocates into the nucleus, where it binds to
transcription factors lymphoid enhancer factor/T cell
factor (LEF-1/TCF) to regulate the transcription of
downstream target genes (29,30).
 RECENT MOLECULAR MECHANISMS OF OSTEOARTHRITIS 247

Figure 1. Molecular mechanisms involved in the development of osteoarthritis including (a) complex cellular interplay in the
articular cavity (mainly synovial inflammation (synovitis) with OA). Synoviocytes (fibroblasts and macrophages) actively synthesize
proteases and cytokines—including IL-6, IL-8, and TNF-α among others—which can negatively affect the articular cartilage.
Degenerative meniscus results in an accelerated progression toward cartilage degradation through elevating inflammatory cytokines,
specifically IL-1 and TNF-α. Chondrocytes may also upregulate apoptosis and ECM degradation, resulting in diminished local
cellularity and eventually, cartilage loss. (b) Molecular mechanisms of articular chondrocyte degenerative changes in OA. The
diagram shows the involvement of receptor ligands such as TGF-β, Indian hedgehog, Wnt-β-catenin, NF-κB signal, and the HIF-2a
signaling pathway, which ultimately activate MMP-13 and ADAMTS, causing cartilage degeneration. (c) Molecular and cellular
interface between chondrocytes and subchondrocytes and osteoblasts at the osteochondral junction in OA. The presence of
connections (microfissures, vascular channels and diffusion) between subchondral bone and cartilage contributes to elevated
crosstalk between chondrocytes. Exposing subchondral bone to cytokines and growth factors from chondrocytes, such as VEGF,
promotes osteoclast activation and increases subchondral bone remodeling, leading to osteoblast abnormality and osteophyte
formation.

Appropriate levels of β-catenin may maintain
moderate maturation of articular chondrocytes
under physiological conditions (31). Both excessive
and insufficient β-catenin levels may destroy the
homeostasis of articular chondrocytes by enhancing
pathological maturation and apoptosis, respectively.
The Wnt/β-catenin signaling pathway induces
MMP13 expression and the expression of aggrecan
through the anabolic factor TGFβ-3, leading to
degeneration and development of OA-like chondro-
cytes (32,33).
Recent findings implied that β-catenin was upregu-
lated in articular cartilage tissue derived from patients
with OA (34). Moreover, protein secreted Frizzled-
related protein (Sfrp)3, a secreted negative regulatory
factor of Wnt signaling, and mutations of the Frizzled-
related protein (FrzB) gene can increase susceptibility to
OA (35). FrzB knockout mice are susceptible to chemi-
cal-induced OA (36). Furthermore, overexpression of
Wnt-induced signaling protein 1 (WISP-1) in the
mouse knee joint also leads to cartilage impairment.
One study has shown that overexpression of β-catenin
in articular cartilage causes abnormal differentiation of
articular chondrocytes, resulting in cartilage degenera-
tion (37).
Effect of Indian hedgehog on articular chondrocyte
degeneration in OA
Indian hedgehog (Ihh), as a member of the hedgehog
protein family, plays a crucial role in chondrocyte pro-
liferation and differentiation (38). In mature articular
cartilage the Ihh signaling pathway also plays a critical
role during OA development. Ihh signaling acts
through two transmembrane receptors: patched (Ptch)
and smoothened (Smo). In the absence of the Ihh
ligand, Ptch binds to Smo leading to inhibition of its
function. Once Ihh signaling is activated, Ihh binds
248 Y. WEI AND L. BAI
Ptch leading to the release of Smo. Smo will further
activate Gli transcription factors to regulate Ihh-
responsive genes (39).
A recent study reported that Ihh is upregulated in
human OA cartilage and synovial fluid, and that the
elevated level correlates with OA progression (40). The
abnormality observed in Ihh–/– mice is an increase in
the fraction of chondrocytes which are post-mitotic,
hypertrophic chondrocytes. This abnormality results
from immature chondrocytes because Ihh–/– cartilage
fails to synthesize parathyroid hormone-related protein
(PTHrP) that keep chondrocytes in the proliferative
phase and correlate with chondrocyte phenotype, spe-
cifically decrease expression of SOX9 leading to
increased COL2A1 (collagen type II, α1) expression
(41,42). Ihh is a critical and possible direct regulator
of joint development. In its absence, distribution and
function of growth and differentiation factor (GDF)5-
expressing interzone-associated cells are abnormal (43).
A mouse genetic study further provided direct evidence
that conditional deletion of Ihh in chondrocytes attenu-
ates OA progression (44). These findings provide
strong evidence that Ihh plays a critical role in OA
pathology, being a central regulator of OA progression,
and raise the possibility that blocking Ihh signaling
could be used as a novel therapy to treat articular
cartilage degeneration in OA.
Effect of hypoxia-inducible factor-2α on articular
chondrocyte degeneration in OA
The HIF proteins belong to a transcription factor
family, and consist of α and β subunit members. HIF-
1 and HIF-2 are key effectors of the cellular response to
hypoxia, and their activity is directly regulated by the
level of oxygen (45,46). Under normoxic conditions,
the proline residues on the α-subunits are hydroxylated;
these are recognized by the von Hippel–Lindau protein
(pVHL) tumor suppressor, an E3 ubiquitin ligase, and
degraded by proteasomes. In contrast, under hypoxic
conditions, HIF-α is not hydroxylated, enabling it to
heterodimerize with β-subunits known as the aryl
hydrocarbon receptor nuclear translocator (ARNT),
ARNT2, ARNT-like (ARNTL), and ARNTL2 to activate
target genes (45,47).
Studies show that the expression levels of HIF-2α are
significantly increased in both human and mouse OA
cartilages (47,48). Due to the lack of vascular tissue in
articular cartilage, chondrocytes in the deeper zones
exist under conditions of low oxygen tension. The
importance of HIF-1 in the formation and maintenance
of cartilage tissue has been demonstrated in conditional
knockout mice in which deletion of the oxygen-
sensitive subunit HIF-1 severely interfered with proper
skeletal development and led to massive cell death
within the center of the forming cartilaginous elements
(49,50). In vitro studies show that HIF-2α is a potent
trans-activator of OA marker genes, including ColX,
MMP13, and VEGF (47). Overexpression of HIF-2α
by intra-articular injection of adenovirus expressing
HIF-2α (Ad-EPAS1), the gene HIF-2α encodes, may
lead to a spontaneous mouse model of OA (29).
Moreover, heterozygous EPAS1-deficient mice have
resistance to surgery-induced OA progression in a
mouse model (47,48). Some studies also suggest that
NF-κB is the upstream inducer of HIF-2α expression
and upregulates NF-κB signaling. HIF-2α binds to β-
catenin and enhances the transcriptional activity of β-
catenin/T cell factor (TCF) by recruiting p300. The
actions of HIF-2α, interestingly, oppose those of HIF-
1α on β-catenin, which suggests that the balance
between HIF-1α and HIF-2β might play an important
role in the cell when hypoxia and Wnt stimulation
coexist (51). These observations suggest that the HIF-
1α/HIF-2α signaling pathway is also involved in OA
development.
Effect of MMP13/Sox 9/ADAMTS on articular
chondrocyte degeneration in OA
Chondrocytes constitute the unique cellular component
of articular cartilage. These cells synthesize the compo-
nents of the extracellular matrix (ECM), including col-
lagens, proteoglycans, and non-collagenous proteins. In
OA, cartilage homeostasis and synthesis of the ECM are
disrupted by many biophysical and biochemical factors.
In this review, the mechanisms described may only
provide insights into the roles of the core factors—
MMP13, ADAMTS, SOX9—in the pathogenesis of OA.
Human clinical and animal studies show that
MMP13 plays a dominant role in the progression of
cartilage degeneration (52). MMP13 is a collagenase
with substrate specificity that targets collagen for degra-
dation. Compared to other MMPs, MMP13 has a more
restricted expression pattern in connective tissue (53).
MMP13 has a much higher catalytic rate than other
MMPs for ColII and gelatin, which makes it the most
potent peptidolytic enzyme among collagenases (29).
MMP13 preferentially cleaves ColII, which is the most
abundant protein in articular cartilage. Cleavage of the
Gly978–Gln979 bond occurs at a specific location (at ¾
length site of type II collagen) (54). MMP-13-overex-
pressing transgenic mice developed spontaneous articu-
lar cartilage destruction characterized by excessive
cleavage of Collagen II and loss of aggrecan (55).
There is considerable evidence that proteolysis of

aggrecan by ADAMTS occurs before and indeed may
be prerequisite for MMP-driven collagenolysis. It is also
apparent that increased cleavage of collagen by MMP-
13. Type II collagen can restrict the swelling pressure of
aggrecan and its loss also lead to the release of aggrecan
and loss of normal viscoelastic function of cartilage
(56). Moreover, the expression of MMP-13 is signifi-
cantly increased in articular cartilage in β-catenin-con-
ditional activation mice (57). These findings implicate
MMP-13 as a critical player in the progression of OA
that could serve as a molecular target for OA therapies.
Sox9 is critical for chondrocyte differentiation and
cartilage morphogenesis during skeletal development
(58). A gene expression study reported that Sox9
expression was lower in human OA cartilage (59).
Sox9, a key chondrogenic transcription factor, plays a
crucial role in the development and maintenance of the
chondrogenic phenotype. Saito T found that the over-
expression of SOX-9 in vitro can mediate the inhibition
of terminal differentiation of chondrocytes and keep it
“fresh” (60). Therefore, modulation of OA cartilage by
genetically modifying the levels of Sox9 expression may
be advantageous in ameliorating the course of OA (61).
ADAMTS are another family of enzymes targeting
collagens and aggrecan for proteolysis, and are major
contributors to cartilage degeneration in OA. Studies
show that there are two types of aggrecanase:
ADAMTS4 and ADAMTS5 (62). Expression and activity
of ADAMTS4 have been shown to be upregulated during
cartilage degeneration, while ADAMTS5 has been shown
to be active in both normal and degenerated cartilages
(63,64). Surgically induced OA experiments performed in
both ADAMTS4 and ADAMTS5 knockout mice showed
that deletion of the ADAMTS5 gene alone relieved carti-
lage degradation, while deletion of the ADAMTS4 gene
could not (64), suggesting that ADAMTS5 may play a
more important role in OA development than
ADAMTS4. In fact, study of ADAMTS5 knockout mice
showed that the protection was due to elimination of
fibrous overgrowth from the periarticular tissues and
deposition of newly synthesized aggrecan in the cartilage
(65). The effect of ADAMTS5 on collagenous tissues may
be revealed by an analysis of Smad-signaling pathways in
wild-type and ADAMTS5-deficient fibroblasts and chon-
drocytes. These animal model studies will definitely influ-
ence strategies employed in the therapeutic control of
human OA in the future.
Inflammatory response and
immunopathogenesis
Since OA is considered a whole joint disease, increasing
evidence has demonstrated the involvement of innate
RECENT MOLECULAR MECHANISMS OF OSTEOARTHRITIS 249
immune system and inflammatory response in the
pathogenesis of the disease. Despite a long history of
categorizing OA as a non-inflammatory form of arthri-
tis, pathologic studies of specimens in the 1980s
described synovial inflammatory infiltrates of mono-
nuclear cells (Figure 1a) (66).
Correlation between synovitis and OA
Despite the different approach employed in the detec-
tion and characterization of synovitis (such as imaging
or histologic assessment) (67–69), published studies
consistently provide evidence of a correlation between
synovial inflammation and symptoms such as pain
(linked to inflammation) in patients with knee OA
(70,71). Scanzello et al. have contributed further evi-
dence of an association between synovitis (defined his-
tologically) and knee symptoms measured by the
Lysholm score (which measures pain, swelling, limping,
locking, instability, and functional disability on a single
scale) in patients with early knee OA undergoing
arthroscopic meniscectomy (72). Synovitis has been
related not only to knee pain but also to knee joint
function, using objective outcome measures of walking
and stair-climbing times (72,73). These efforts have
provided substantial evidence that synovitis is asso-
ciated with major symptoms such as pain and degree
of joint dysfunction, and may promote more rapid
cartilage degeneration (69,74).
Innate immunity of synovial inflammation
(synovitis) in OA (Table 1)
Monocytes/macrophages and other cells of the
innate immune system in OA
Macrophages are among the most abundant cell types
present in cellular infiltrates found in the inflamed
synovium of OA patients (75,76). Monocyte subsets,
classic, intermediate, and nonclassic, play a major
homeostatic role in tissue remodeling and mainte-
nance, facilitated by apoptotic “eat me” opsonins like
C-reactive protein (CRP), serum amyloid P, C1q, C3b,
IgM, ficolin, and surfactant proteins (77). Monocyte
chemoattractant protein 1 (CCL2 or MCP-1) is one of
the most important chemokines regulating systemic
and local cell trafficking and infiltration of monocyte/
macrophages in chronic inflammation. Blocking CCL2-
CCR2/CCR4 ligand–receptor axis using 7ND, a mutant
CCL2 protein, can reduce migration of monocytes/
macrophages in vitro (78). Using a collagenase-induced
mouse model, Bondeson et al. found several chemo-
kines responsible for chemotaxis of macrophages in the
development of OA, such as TGF-β and interleukin
250 Y. WEI AND L. BAI

Table 1. Molecular factors of inflammatory response and immunopathogenesis of Osteoarthritis (OA).

Expression represents duration of synovial
Molecular factors Function in OA procession inflammation in OA References
TGF-β responsible for chemotaxis and activation of macrophages Innate immunity of Synovial Inflammation in (75)
IL-1β OA (76)
IL-6 (77)
IL-8
MMP-1 (77)
MMP-3
TLRs a group of motif recognition receptors important in eliciting (85–87)
an initial innate response
decay accelerating factor activation of complement-mediated response Activation of complement system of Synovial (92)
(DAF) Inflammation in OA
C5b-9 terminal complement (93)
complex
fibromodulin positive affect complement cascade activity (100)
cartilage oligomeric matrix (101)
protein (COMP)
osteoadherin (102)
collagen IX inhibitors of complement cascade activity (103)
MAC complex maybe a protection in development of OA (104)
IL-1 relive the clinical symptom Cytokines of Synovial Inflammation in OA (108)
NALP3 inflammasome et al. Responsible for IL-1 activation (109)
TNF-α participates in chondrocyte destruction and pain symptom (112,113)
IL-6 pro-inflammatory cytokines in the development of OA (104)
IL-7
IL-8
leukemia inhibitory factor
(LIF)
IL-11
IL-17
IL-18
oncostatin M(OSM)
IL-4, anti-inflammatory cytokines in the development of OA
IL-10
IL-13
IL-8/CXCL-8 induce hypertrophic differentiation and calcification in Chemokines of Synovial Inflammation in OA (63)
GRO-α/CXCL-1 chondrocytes
RANTES/CCL-5 and its induced normal chondrocytes collageⅡdegradation
receptors
CCR7 a role in synovial angiogenesis when OA starting (67)
CCL19
MIP-1γ/CCL-9 increased formation of osteoclasts in joints (115)

(IL)-1β (79,80). Macrophage depletion also resulted in
decreased production of IL-6, IL-8, MMP-1, and MMP-
3 (81). These findings suggest that activation of syno-
vial macrophage is required for the production of
MMPs leading to cartilage damage (82–85). Natural
killer cells have also been obtained from synovial tis-
sues of patients undergoing total joint replacements,
but the mechanism of pathogenesis has not yet been
elucidated in detail (86).
Activation of the innate response often begins with
the stimulation of pattern-recognition receptors
(PRRs), classically in the setting of infectious insult by
microbial ligands (87). However, Under OA progres-
sion, PRRs can be activated by endogenous damage-
associated molecular patterns (DAMPS) such as hyalur-
onan, rather than by microbial ligands (88). TLRs
(TLR1 through 10 in humans) are a group of motif
recognition receptors important in eliciting an initial
innate response against pathogens. TLRs are constitu-
tively expressed on macrophages mostly (89). TLRs 1–7
and 9 have been detected in SM in OA (90,91). TLR
activation in the SM is an important stimulus for
recruiting and activating macrophages, granulocytes
and lymphocytes (92). Evidence has suggested that a
number of endogenous products, produced by matrix
disruption or cellular stress, can also bind and activate
TLRs. Many putative TLR ligands are modified in form
or distribution, or increased in concentration in joint
fluids or tissues in the setting of OA joint (93). The
regulatory processes involved in TLR activation are
complex, and their role in promoting synovitis in OA
is not fully established. However, targeting TLRs,
ligands, and pathways that trigger their activation
need to be explored as potential therapeutic approaches
in OA.
Activation of the complement system in synovial
inflammation (synovitis) in OA
The complement system, including a cascade of pro-
teins, constitutes an important effector mechanism in
the immune system to eliminate pathogens and
immune complexes. The deposition and activation of

complement factors in OA cartilage have been docu-
mented in several studies in OA patients as well as in
animal models of OA (94,95). Tarkowski et al. observed
expression of decay accelerating factor (DAF) in the
synovial lining cell layer in OA along with C5b-9 term-
inal complement complex suggesting activation of a
complement-mediated response (96,97). However,
blood or serum leaking into the joint after injury pro-
vide a source of complement proteins in many patients
(98–101), and as early as 1988, Corvetta et al. found
complement deposition in synovial membranes follow-
ing meniscal tears or cartilage degeneration (102).
Chondrocytes and synovial macrophages may also
actively produce complement components and inhibi-
tors (97,103). Complement components and immuno-
globulins have been identified in synovial fluid from
OA patients using proteomic approaches (98). Several
studies have also demonstrated that other molecular
components in the articular cartilage may affect com-
plement cascade activity, such as fibromodulin (104),
cartilage oligomeric matrix protein (COMP) (105), or
osteoadherin (106). In contrast, collagen IX, properdin,
and CD59 can act as inhibitors of complement (107). In
recent studies, mice with impaired ability to generate
the complement membrane attack complex (MAC)
were partially spared from the development of OA,
showing direct evidence of role of complement system
in OA pathogenesis (108). However, the way comple-
ment deposition occur in joint synovium of OA, and
the role of the complement cascade in the pathogenesis
remain to be precisely determined.
Role of cytokines in the synovial inflammation of OA
PPRs and activation of the complement cascade result in
the release of several soluble factors such as cytokines (IL-
1, TNF-α, etc.) and chemokines (IL-8, CCL5, CCL19, and
its receptor CCR7) from the synovium causing further
progression of OA symptoms (109). During OA, these
mediators may be produced by a variety of cell types,
including macrophages, chondrocytes, and synovial fibro-
blasts (110). Such cytokines as synovial factors have
shown much potential to induce cartilage destruction in
vitro (111). Some specific examples will be introduced
below with respect to synovial inflammation in OA.
IL-1. Although IL-1 has significant effects on articular
cartilage destruction, IL-1 is not consistently elevated in
the synovial fluid of OA patients (10). Attempts to block
IL-1 activity therapeutically in patients have been asso-
ciated with relief of the clinical symptom until 3 months
(112); articular cartilage destruction was not improved.
However, it is possible that IL-1 activity may be important
in specific clinical settings of OA. The endogenous IL-1
RECENT MOLECULAR MECHANISMS OF OSTEOARTHRITIS 251
receptor antagonist, which blocks IL-1 activity, is produced
by synoviocytes at higher levels in OA (98). Production of
active IL-1 requires activation of the NALP3 inflamma-
some by agonists such as crystals including basic calcium
phosphate (113) and hydroxyapatite (114). Crystal
Deposition of both hydroxyapatite and basic calcium phos-
phate occurs in patients with OA. Therefore, it is predicted
that IL-1 may be an important effector of crystalline and
other crystals’ (basic calcium phosphate and hydroxyapa-
tite) deposition in patients with OA.
Tumor Necrosis Factor (TNF)-α. TNF-α was identified
in the SF of patients with OA as early as in 1996.
Although TNF-α is elevated in OA, it is not as high
as that seen in RA. (115). TNF also participates in
chondrocyte destruction (116). Evidence suggested
that the synovium supernatants TNF-α concentrations
were significantly higher in supernatants from cultured
OA synovium as compared with non-arthritic (NA)
synovium (117). TNF receptor (TNF-R) becomes upre-
gulated on chondrocytes in cartilage from specific
regions (118). The answer may lie in the differences
in weight bearing experienced by chondrocytes in car-
tilage from different regions of the joint. Loading has a
profound effect on chondrocyte metabolism. Magnano
et al. reported the results of a trial of a TNF-inhibitor in
an open-label pilot study to treat pain and inflamma-
tion in twelve patients with OA (119). Like the IL-1
trials, this trial did not demonstrate apparent improve-
ment, but nevertheless improvements in pain and phy-
sical function scores were reported by some individuals.
This may reflect a more complex interplay involving
various pathogenic factors in OA.
Other cytokines. The study of the roles of other pro-
inflammatory cytokines, including IL-6, oncostatin M
(OSM), IL-7, IL-8, leukemia inhibitory factor (LIF), IL-
11, IL-17, IL-18, and anti-inflammatory cytokines
including IL-4, IL-10 and IL-13, show that synovial
inflammation impacts on chondrocyte metabolism,
and hence, favoring the development of OA (110).
Chemokines. Chemokines are small secreted mole-
cules responsible for chemotaxis of immune cells
and thus play an important role in the immune sys-
tem. Scanzello demonstrated that synovial inflamma-
tory infiltrates were associated with expression of a
distinct mRNA chemokine in patients with OA. The
chemokine included IL-8, CCL5, CCL19, and its
receptor CCR7 (72). Merz et al. showed that IL-8/
CXCL-8 may induce hypertrophic differentiation and
calcification of chondrocytes (120). While CCR7 is
expressed by synovial fibroblasts, and, when activated
252 Y. WEI AND L. BAI
by its ligand CCL19, mediates upregulation of vascu-
lar endothelial growth factor (VEGF), implying a role
in synovial angiogenesis in the early stages of OA
(79). CCR5 together with its ligand CCL-21 plays a
similar role to CCL19. MIP-1γ/CCL-9 has been
shown to be produced by activated CD4+ T cells
present in the synovium of a mouse model of OA,
which also resulted in increased formation of osteo-
clasts in the joints (121). In summary, chemokines
represent a class of soluble inflammatory mediators
that have pleiotropic effects on joint tissues, and may
contribute to inflammation and clinical symptoms in
patients with OA.
Role of inflammatory signal NF-κB in OA
The abundant form of NF-κB is a heterodimer of p65/
RelA and p50. In the resting state, this is bound to the
inhibitory protein IκB of which αorβ are the major
forms. The trimeric complex in mainly cytoplasm.
When a signaling complex forms, it activates the κB
kinase (IKK) component of the IKK complex. The IKK
complex is also a trimer and comprises IKKα and β,
together with IKKγ. IKKγ is an important adaptor
enabling the receptor signaling complexes to activate
the IKKβ. IKKβ phosphorylates IκBα at Ser32 and
Ser36. The phosphorylations target the κB for rapid
ubiquitination and degradation. This removes the
nuclear export signal of the inhibitor and unmasks a
nuclear localization signal on the p65 subunit. The NF-
κB dimer therefore locates mainly in the nucleus where
it binds to specific sites in the promoter regions of
sensitive genes and promotes transcription (122). NF-
κB transcription factors can be triggered by a host of
stress-related stimuli like pro-inflammatory cytokines
IL-1 (123); indeed, through the canonical NF-κB path-
way to trigger the expression of metalloproteinases
(MMPs), prostaglandin E2 (PGE2), nitric oxide (NO),
and type X collagen in chondrocytes (124,125), leading
to increased cartilage degradation and chondrocyte
hypertrophy in OA cartilage.
Role of meniscus in the synovial inflammation of
OA
The clinical importance of the meniscus in OA devel-
opment is well documented (126–128). However,
meniscus pathology in OA is largely attributed to
mechanically mediated loss of structural integrity.
Accumulating evidence supports that knee OA progres-
sion is often driven by biomechanical forces, and the
pathological response of tissues to such forces leads to
structural joint deterioration, knee symptoms, and
reduced function. The addition of elevated inflamma-
tion at the time of meniscal damage or meniscal degen-
eration results in an accelerated progression toward
cartilage degradation. Shortly after a meniscus rupture,
inflammatory cytokines, specifically IL-1 and TNF-α,
are upregulated in the joint, indicating an inflammatory
response (129). Specifically, Scanzello et al. also found
that synovial IL-15 is elevated in degenerative meniscal
tear patients with Kellgren–Lawrence grade 1 or 2
compared to end-stage OA patients undergoing total
knee replacement (130). Hellio Le Graverand et al. used
ACL-transected rabbits as an OA initiation model in
order to measure inflammatory expression changes in
the early stages during which the meniscus is degener-
ating. This study found that while meniscal expression
of TNF-α was downregulated, the inflammatory
enzyme COX-2 (cyclooxygenase-2) was upregulated in
the medial meniscus 3 weeks after ACL transaction,
indicating an inflammatory response in the degenerat-
ing meniscus during the early stages of OA develop-
ment. Thus, elevated levels of inflammation may be
present during meniscal degeneration (131). Meniscal
cells are also responsive to cytokine stimulation like IL-
1β, IL-6, and TGF-α with increased proteoglycan and
nitric oxide release (132). The degenerated menisci
show significant upregulated expression of ADAMTS
and MMPs following cytokine stimulation, which con-
tributed to cartilage degeneration (133). These pieces of
evidence suggest that the addition of elevated inflam-
mation at the time of meniscal damage or meniscal
degeneration results in an accelerated progression
toward cartilage degradation. Cell adhesion markers
such as vascular cell adhesion molecule (VCAM)-1,
intercellular adhesion molecule (ICAM)-1, and
E-selectin were also increased in the degenerative
menisci and were to be present in hypertrophic and
early osteoarthritic synoviumn and were involved in
inflammatory cell recruitment to the synovium
(134,135).
Pathogenic role of metabolic triggered
inflammation in OA
The incidence of obesity worldwide has increased dra-
matically in recent decades. Accordingly, obesity and
associated disorders such as OA now constitute a ser-
ious threat to the current and future health of both
developed and developing populations. A newly
defined phenotype of OA, “metabolic OA,” has been
associated with metabolic syndrome (MetS) and obesity
(136). Metabolic triggered inflammation also called
meta-inflammation (137) is mainly caused by nutrient
overload and metabolic surplus (138). Metabolic
 RECENT MOLECULAR MECHANISMS OF OSTEOARTHRITIS 253

overload results in oxidative stress and inflammation, Subchondral osteoblasts have an abnormal
which then triggers vicious stress cycles that lead to cell phenotype in OA
dysfunction (139). The components that make up the
Subchondral bone sclerosis is characterized by trabecu-
cluster of MetS, such as overweight, dyslipidemia, and
lar thickening, an increase in osteoid volume, and a
impaired glucose tolerance, have been involved in
decrease in calcium binding to collagen fibers. This
meta-inflammation (140). Meta-inflammation usually
abnormal mineralization is due to the overproduction
is a type of chronic inflammation presenting elevated
of the homotrimeric α1 form of type I collagen by
levels of cytokines, acute-phase inflammatory compo-
osteoblasts. This (α1)3 type I collagen has lower affinity
nents (complements and CRP), and other mediators
for calcium than (α1)2 type I collagen (152,153).
(141,142). Furthermore, adipocytes, as the key cell of
Increasing evidence suggests that OA osteoblasts
meta-inflammation, also synthesize numerous cyto-
showed a decreased cAMP response to PTH and an
kines such as IL-6, IL-1, and TNF-α and adipokines
increased production of alkaline phosphatase and
such as leptin, adiponectin, resistin, and visfatin (143).
osteocalcin in response to vitamin D3. Further, under
Excessively secreted factors could disturb the integra-
basal conditions, OA osteoblasts produce more insulin-
tion of systemic metabolism, thereby leading to inflam-
like growth factor-1 and urokinase than normal cells. It
matory response. In addition, some local fat tissues,
has also been reported that subchondral bone explants
such as infra-patellar fat pad (IPFP), may act as mod-
from OA patients produce more IL-6, IL-8, and MMP-
ulators in OA. IPFP was considered a source of local
13 (154) as well as osteopontin, osteocalcin, TGF-β1,
inflammatory mediators and thus an active osteoar-
type I collagen, IL-6, IL-8, and high levels of alkaline
thritic tissue (144), but it also has a beneficial effect
phosphatase (ALP) but downregulated osteoprotegerin
possibly through biomechanical mechanisms, as sup-
(OPG) gene expression and protein production (155–
ported by a recent study suggesting that IPFP size was
157). IL-6 and PGE2 stimulate receptor activator of
negatively associated with OA disease severity indepen-
nuclear factor Kappa-B-/Ligand (RANKL) and inhibit
dent of BMI and total body fat (145).
OPG production by osteoblasts and thus increase
osteoclast differentiation and activation via their effect
Subchondral bone changes in OA on the RANK/RANKL/OPG system (158,159). These
factors play a dominant role in osteoclastic activity.
Subchondral bone plays a critical role in OA progres-
Therefore, the bone-forming activity of subchondral
sion. The term subchondral bone refers to a layer of
bone cannot be accompanied by equivalent mineraliza-
bone immediately beneath the cartilage and is formed
tion. In addition, osteoblast showed an increased
by a 6-mm layer of trabecular bone plate. Anatomically,
expression of MMP-1which would account for degra-
the subchondral bone consists of both a subchondral
dation of non-mineralized collagen type I in SBC (160).
cortical plate and a layer of cancellous bone. The sub-
These studies suggest that the formation of unminer-
chondral cortical plate is in nature similar to other
alized, immature new bone leads to the appearance of
cortical bone, while subchondral cancellous bone has
abundant osteoids and bone cysts in OA.
a lower volume, density, and stiffness than the cortical
plate (146). However, based on the available evidence,
there is no consensus on subchondral bone changes in
Cartilage interface with subchondral bone in OA
early OA. Some studies have previously suggested that a
thickening of the growth plate is occurring as a primary In OA, chondrocytes are stimulated to express molecules
fundamental subchondral bone change in OA (147). It that are associated with chondrocyte hypertrophy and
has also been demonstrated in animal studies that thin- terminal differentiation, such as VEGF, runt-related tran-
ning of the subchondral bone occurred before cartilage scription factor 2 (RUNX2) and MMP-13. Secretion of
damage was detected, suggesting that bone turnover angiogenic factors such as VEGF increases vascularity
may be increased in the early stages of OA (148). within the deep layers of articular cartilage, thus facilitat-
Surely, changes to subchondral bone in the progressive ing molecular transport. Recently, the communication
stages of OA are characterized by extensive remodeling pathways of cartilage effect on bone reported includes
of the trabeculae, formation of new bone below new microcracks, neovascularization, vascular channels next
cartilage (osteophytes), and the development of sub- to the cruciate ligaments, in addition, small molecules
chondral bone cysts (SBC) (149–151). Like cartilage, diffusion directly (161,162). Chemokines, cytokines, and
an increase in expression level of certain genes in proteases secreted by chondrocytes have been implicated
bone is regarded as a biochemical marker of OA in the alteration of biochemical and functional abilities of
(Figure 1c). the osteoblasts within subchondral bone. For example, IL-
254 Y. WEI AND L. BAI
6 in combination with other cytokines such as IL-1β can
switch osteoblasts from a normal phenotype to a sclerotic
phenotype (162,163). There is increasing evidence that
the Wnt signaling pathway is a key regulator of subchon-
dral bone and is implicated in OA (164). In an animal
model of OA, Wnt activation was predominantly
observed in osteocytes of the subchondral bone. Altered
activity of Wnt signaling in chondrocytes may involve
osteoclastic activity in subchondral bone growth plates
leading to sclerosis or osteophyte formation at the edges
of joints (165,166). In addition, Dickkopf-1 (Dkk1) is an
inhibitor of this pathway, and its overexpression in bone
leads to thicker and stiffer bones, retarding cartilage
degradation (167). Moreover, the deletion of sclerostin,
another Wnt antagonist, increased the severity of OA,
although no changes in cartilage were observed (168).
Dkk2 is regulated by vitamin D and TGFβ expression
was increased and both contributed to the abnormal
osteoblast phenotype in OA, which implied that TGFβ is
another key factor involved in development of bone
abnormalities during OA, promoting both osteophyte
growth and subchondral bone formation (169,170).
Lastly, numerous factors in the subchondral bone envir-
onment have been identified as pathogenic factors affect-
ing cartilage and could therefore be potential therapeutic
targets in OA.
Conclusions and perspectives
Collective evidence indicates that OA is not simply a
process of wear and tear but a disease with more com-
plex etiology, more risk factors and more molecular
mechanisms resulting in organ failure of the entire
joint. Among the molecular mechanisms, degeneration
of articular cartilage, synovial immunopathogenesis,
and changes in subchondral bone are key factors in
the mechanisms leading to joint damage in OA. Thus,
synovial change, cartilage and subchondral bone para-
meters assessed by imaging techniques, or biochemical
markers may soon help the clinician to identify differ-
ent specific OA phenotypes. This stratification strategy
is likely to expand the options for clinicians to use
comprehensive methods to evaluate and treat OA
patients. Novel drugs and agents that specifically
block the mechanisms involved in synovial inflamma-
tion can potentially protect against degeneration of
articular cartilage and prevent subchondral bone remo-
deling responsible for the osteoarthritic changes,
thereby enabling targeted therapy to be developed.
These comprehensive agents will benefit suffering
patients and provide exciting new hope for the treat-
ment of OA.
It is true that in past decades, increased knowledge of
the detailed molecular and signaling pathways involved
in OA development has enabled significant progress to
be made which has even been applied to clinical treat-
ment. However, what is the exact pattern of degradation?
What tissue is the lead problem in the early stage of OA?
How do tissues respond in later stages? More exact pre-
cision mechanisms need to be further explored. In addi-
tion, in the clinic, many patients suffering similar degrees
of OA received the same drug and physical treatments,
but surprisingly, different outcomes were observed. This
shows that there are differences in OA-related genes
between individuals. Recent advances in epigenetic stu-
dies have shed light on the importance of epigenetic
regulation of gene expression in the development of
OA. Microarray-based gene expression studies and net-
work-based analysis, along with epigenetic analysis, are
essential for the identification of signaling pathways
regulated during disease development. The epigenetic
findings may not only broaden our understanding of
the molecular mechanisms underlying the development
of OA, but also promote the development of new drugs
for the treatment of OA. In the future, individualized and
comprehensive treatment will be applied to the interven-
tion of OA.
Financial support
This work is supported by National Natural Science
Foundation of China (General Program; Grant
Number: 81272050).
Declaration of interest
The authors declare no competing interests.
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