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J Recept Signal Transduct Res, 2014; 34(2): 73–80

! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2013.863919

REVIEW ARTICLE

WNT signaling and chondrocytes: from cell fate determination to

osteoarthritis physiopathology
Nadia Sassi1, Lilia Laadhar1, Mohamed Allouche2, Asma Achek1, Mariem Kallel-Sellami1, Sondès Makni1, and
Slaheddine Sellami1
1
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Immuno-Rheumatology Research Laboratory, Rheumatology Department, La Rabta Hospital, University of Tunis-El Manar, Tunis, Tunisia and
2
Forensics Department, Charles Nicolle Hospital, Tunis, Tunisia

Abstract Keywords
Context: Osteoarthritis (OA) is an articular disorder leading to the degradation of articular Articular cartilage, chondrocyte, collagens,
Journal of Receptors and Signal Transduction 2014.34:73-80.

cartilage phenotypical chondrocytes modifications, including the acquisition of a fibroblast-like osteoarthritis, WNT signaling
morphology, decreased expression of collagen type II, and increased expression of fetal
collagen type I, metalloproteinase 13 and nitric oxide synthase. This promotes matrix History
degradation and unsuccessful cartilage repair. WNT signaling constitutes one of the most
critical biological processes during cell fate assignment and homeostasis. Objectives: This review Received 31 August 2013
aims to give an insight on results from the studies that were interested in the involvement of Accepted 5 November 2013
WNT in OA. Methods: Studies were selected through a pubmed search. Results: Recent genetic Published online 4 December 2013
data showed that aberration in WNT signaling may be involved in OA. WNT signals are
transduced through at least three cascades: the canonical WNT/b-catenin pathway, the WNT/
Ca2þ pathway and the WNT/planar cell polarity pathway. Most of the studies used in-vitro
models to elucidate the involvement of WNT in the physiopathology of OA. These studies
analyzed the expression pattern of WNT pathway components during OA such as WNT5, WNT7,
co-receptor LRP, b-catenin, WNT target genes (c-jun, cyclins) and/or the interaction of these
components with the secretion of OA most important markers such as IL-1, collagens, MMPs.
Results from these studies are in favor of a deep involvement of the WNT signaling in the
physiopathology of OA either by having a protective or a destructive role. Conclusion: Deeper
researches may eventually allow scientists to target WNT pathway in order to help develop
efficient therapeutic approaches to treat OA.

Introduction modifications promote matrix degradation and unsuccessful

cartilage repair (4,5).
Osteoarthritis (OA) is the most prevalent articular disorder and
WNT signaling is a conserved pathway involved in
it is increasingly becoming a major health problem with the
aging of the populations (1). OA results in the degradation of
cell differentiation and fate determination during embryo- 14
20
genesis and late stages of development. WNT signaling
articular cartilage leading to joint dysfunction. In fact, during
constitutes one of the most critical biological processes
the pathology, degradation of the extracellular matrix exceeds
during cell fate assignment (6,7). WNTs are secreted
its synthesis, resulting in a decrease in the amount of cartilage
glycoproteins that bind to transmembrane receptors called
matrix and the erosion of joint surfaces (2,3). Besides,
‘‘frizzled’’ (fzl). WNT proteins (from WNT 1 to WNT 19)
chondrocytes undergo phenotypic modifications, including
also interact with co-receptors of the ‘‘low density
the acquisition of a fibroblast-like morphology, loss of the
lipoprotein-related protein’’ (LRP) family. These co-
ability to express collagen type II (colII), and increased
receptors allow other WNT pathway mediators to bind
expression of fetal collagen type I (colI), metalloproteinase 13
too such as Dickkopf protein (DKK).
(MMP13) and nitric oxide synthase (NOS); usually known
WNT signals are transduced through at least three distinct
as chondrocyte ‘‘de-differentiation.’’ These phenotypical
intracellular signaling pathways including the canonical
WNT/b-Catenin pathway, the WNT/Ca2þ pathway and the
WNT/Planar Cell Polarity (PCP) pathway.
Address for correspondence: Nadia Sassi, Immuno-Rheumatology WNT signaling is essential for bone homeostasis and its
Research Laboratory, Department of Rheumatology, La Rabta
Hospital, 1007 Tunis, Tunisia. Tel/Fax: +21671560432. E-mail: effects in chondrogenic differentiation and cartilage formation
nadiasassitn@yahoo.com are complex (8). WNT signaling can also promote cartilage
 74 N. Sassi et al.
degradation by activation of catabolic genes in chondrocytes
(9). Recent genetic data showed that aberration in WNT
signaling may be involved in OA (10).
Besides, it has been shown in a murin model that
deficiency in WNT antagonist Frzb gene leads to high
susceptibility to OA (11).
Recent studies further suggest the relevance of WNT
signaling in human OA (12).
Historical background of the WNT genes
Thirty-one years ago, for the first time, Nusse and Varmus
characterized the int1 locus as the integration site of the
mouse mammary tumor virus (13). Five years later, this locus
was shown to be the wingless drosophila homologue (14).
Nowadays, more than 19 WNT genes were identified with
27–83% sequence homology.
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WNT genes have been characterized in vertebrates and
invertebrates but seem to be inexistent in unicellular eukary-
otes, plants and prokaryotes (15). The vertebrates usually
share more than 90% homology in the sequence of the WNT
genes between the species.
The WNT gene encodes for secreted proteins involved in
Journal of Receptors and Signal Transduction 2014.34:73-80.
intracellular signaling. These proteins play crucial roles in
cell differentiation during development (16).
WNTs are 39–46 kDa proteins with cystein rich domains
(23 or 24 residues) and 350–400 amino acids with N-terminal
peptide (15,17). In mammals, 19 WNT proteins were
identified. Murine WNT3a protein was the first biochemically
characterized one (18).
The major components of the WNT pathway
WNT signal transduction needs binding to one of two family
receptors: the fzl family and the LRP family (19). Receptor fzl
was identified in drosophila and then several homologues
were identified in vertebrates (20,21). Fzl receptors consist
of 7 types belonging to the G-protein-coupled-receptor
family (22). The extracellular N-terminal side of fzl contains
a cystein rich domain able to directly interact with WNT
protein. The intracellular C-terminal domain of fzl contains
a conserved sequence that interacts with another signal
mediator named ‘‘dishevelled’’ (dsh) (23).
LRP is considered as fzl co-receptor (24). It is a
transmembrane protein with an extracellular epidermal
growth factor-like (EGF-like) domain involved in WNT
protein binding and signal transduction (25). The cytoplasmic
C-terminal domain contains five conserved sequences
required for WNT signal transduction.
At the extracellular side, some WNT antagonists have been
characterized. The secreted frizzled related protein (sFRP)
and the ‘‘WNT inhibitory factor’’ (WIF) act by sequestration
of the WNT protein in the extracellular matrix thus
blocking signal transduction cascade. There are four sFRP
types (1–4) which bind to the WNT protein via the
cystein-rich domain. WIF binds to WNT proteins by a
140 residues domain named ‘‘wif’’ (26,27,28). There are
other extracellular inhibitors such as: ‘‘WNT-modulator in
surface ectoderm’’ (WISE) (29), sclerostine (SOST) (30,31)
and DKK (32). These inhibitors antagonize WNT signaling
by interacting with co-receptor LRP. DKK, for instance,
J Recept Signal Transduct Res, 2014; 34(2): 73–80
acts like a bridge between LRP and another transmembrane
protein called ‘‘kremen’’ leading to LRP endocytosis (33).
In the cytoplasm, several proteins are involved in the
WNT cascade. Dsh, a downstream of fzl, is recruited by the
C-terminal side of the receptor leading to its phosphorylation
(34,23). Another protein called axin interacts with the
C-terminal domain of co-receptor LRP and antagonizes
WNT signaling at the intracellular level (35). WNT protein
binding to LRP leads to phosphorylation of the latter and
creates an attachment site for axin (25). Axin association with
other cytoplasmic proteins such as The ‘‘Adenomatous
Polyposis coli’’ (APC) form a b-catenin inhibiting complex.
APC is an intracellular protein that is responsible for reducing
cytoplasmic b-catenin levels. APC is known to be a tumor
repressing protein since it is usually mutated in colorectal
cancer (36,37,38). b-Catenin is the key mediator of the WNT
‘‘canonical’’ cascade. Other than being involved in WNT
signaling, b-catenin, in association with cadherins, plays
critical roles in cell–cell interactions and cellular adhesion. It
acts in association with a-catenin and binds to the actin
network and cadherins. The b-catenin levels responsible for
either WNT signaling or cell adhesion are constantly balanced
(16) (Figure 1a).
Activation of the WNT pathway
Soluble WNT proteins activate the pathway by binding to
receptor fzl. This interaction can transmit signals via at least
three distinct cascades according to the involvement of
b-catenin protein. They can be classified as: the canonical
WNT/b-catenin signaling or the non-canonical WNT/Ca2þ
and WNT/PCP signaling. The non-canonical cascades are
activated independently of nuclear b-catenin leading to
different phenotypical responses (15,39–42).
WNT soluble proteins are the initiators of the pathway
but have distinct effects on their target. Some of these proteins
are responsible for the activation of the WNT/b-catenin
signaling whereas others are responsible for WNT/Ca2þ/PCP
activation.
b-catenin-dependent activation of the WNT pathway
(the canonical signaling)
Cells stimulation by WNT protein induces Dsh recruitment at
the membrane and blocking the axin inhibiting complex.
These events result in the release of b-catenin which
translocates to the nucleus where it forms dimers with the
‘‘LEF/TCF’’ DNA binding factors (lymphoid enhancer factor
1/T-cell factor) (43).
Wu et al. (2008) showed that since b-catenin does not
contain a nuclear localization sequence, the translocation is
controlled by the phosphorylation of the protein (44). Once
in the nucleus, b-catenin interacts with the LEF/TCF family
of transcription factors (45,46). The LEF/TCF family is
composed of TCF-1, LEF-1, TCF-3 and TCF-4. In the
absence of b-catenin, these factors are responsible for the
active recruitment of corepressors: ‘‘CtBP’’ (C-terminal
binding protein), ‘‘HDAC1’’ (histone deacetylases 1) and
‘‘Groucho/TLE’’ (Groucho/transducin-like enhancer of split)
(47–51). When b-catenin is in the nucleus it binds to TCF
with its armadillo repeats, displaces the ‘‘Groucho/TLE’’
 DOI: 10.3109/10799893.2013.863919
corepressor and recruits coactivators via the N-terminal and
the C-terminal domains (52). The N-terminal domain directly
interacts with ‘‘BCL9/legless’’ (B cell lymphoma 9/legless)
which recruits a coactivator called ‘‘Pygopus’’ (53–56). The
latter contains a ‘‘PHD’’ domain (Plant homeodomain) able
to interact with tri-methylated histones leading to epigenetic
modification of the target genes (57). The C-terminal domain
of the b-catenin recruits the ‘‘p300/CBP’’ (E1A binding
protein p300/CREB-binding protein) complex essential for
WNT signaling (58,59). p300 and CBP are transcriptional
coactivators responsible for acetylating histones leading to
loosen the chromatine and recruiting other transcription
factors to initiate the transcription of the WNT target genes
(60,61). The most known WNT target genes are c-jun and
cyclins which are especially involved in cell proliferation
(25,62–66).
b-catenin may also interact with coactivator ‘‘FHL2’’ (four
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and a half LIM domains protein 2), transcription factor
‘‘TBP’’ (TATA-binding protein), ‘‘Brg1’’ (Brahma related
gene 1) and TIP49a/Pontin52 (TBP-interacting protein 49a/
Pontin52) (67–70) (Figure 1b).
Journal of Receptors and Signal Transduction 2014.34:73-80.
b-Catenin-independent activation of the WNT path-
way (the non-canonical signaling)
Non-canonical WNT signaling does not involve the b-catenin
protein. In certain conditions, it even induces b-catenin
inhibition (71). Non-canonical WNT is associated with cell
movements and motility and the anteroposterior extension of
the body axis (72). This signaling is characterized by the
ability to antagonize the WNT/b-catenin pathway. It has been
shown that hyper-expression of WNT5a (a non-canonical
effector) in Xenopus embryo results in blocking the induction
of the secondary axis due to the ectopic expression of WNT8
(a canonical effector) (73).
Figure 1. (a) Components of the WNT pathway when it is inactive, (b) activation of the WNT/b-catenin cascade. sFRP: secreted related frizzled
protein; LRP: low-density lipoprotein-related protein; DKK: dickkopf; APC: adenomatous polyposis coli; Dsh: disheveled; GSK: guanosine kinase;
HDAC: histone deacetylase; Gro: Groucho gene; TCF: T cell factor; LEF: lymphoide enhancer factor; CtBP: C-terminal binding protein; b-TrCP:
F-box/WD repeat-containing protein; P: phosphate; Bcl9: B-cell CLL/lymphoma 9 protein; Pygo:Pygopus: P300/CBP: E1A binding protein p300/
CREB-binding protein.
WNT signaling and chondrocytes 75
The non-canonical signaling can be classified according to
the molecules involved in the cascades: WNT/PCP through
‘‘Rho’’ and ‘‘JNK’’ (c-jun N-terminal kinase), and WNT/
Ca2þ through PKC (protein kinase C) and CaMKII (calcium/
calmodulin-dependent kinase II) (74,75).
The PCP pathway is involved in cellular asymmetry of
epithelial tissues and sensory organs (72,76). Mutations of the
PCP pathway are associated with disruption of neural
development (77,78). The activation of this cascade begins
when WNT protein binds exclusively to receptor fzl
(co-receptor LRP does not play a role in this process) leading
to the activation of Dsh protein and its association to Daam1
protein (Dsh associated activator of morphogenesis 1). These
events are responsible for activating GTPases: Rho and Rac.
The latter stimulate JNK cascade. The downstream process is
not clarified although Rho and Rac activation is known to be
involved in cell polarization and motility (79,80) (Figure 2a).
The Ca2þ non-canonical signaling is activated when WNT
binds to fzl and activates the PLC (phospholipase C) leading
to an increase in the cytoplasmic concentration of Ca2þ. The
changes in Ca2þ activate calcium-dependent proteins such as
PKC and CaMKII. The latter is responsible for the activation
of transcription factors: NFAT (nuclear factor of activated
T cell), TAK1 (TGF-b activated kinase) and NLK (nemo-like
kinase), known to induce the reduction of intracellular cGMP
and thus blocking the WNT/b-catenin/TCF signaling (81,82).
The WNT/Ca2þ signaling is involved in many developmental
processes including cytosqueletal organization and cell
adhesion regulation (83) (Figure 2b).
WNT signaling during early stages of cartilage
development
Cartilage development starts with chondrogenesis and
requires the formation of mesenchymal condensations.
 76 N. Sassi et al.
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Figure 2. (a) activation of the WNT/Ca2þ pathway, (b) activation of the WNT/PCP pathway. LRP: Low-density lipoprotein-related protein; PLC:
phospholipase C; PKC: protéine kinase C; Ca2þ: calcium 2þ, CamKII: Ca(2þ)/calmodulin-dependent protein kinase; Dsh: disheveled; Daam1: Dsh
Journal of Receptors and Signal Transduction 2014.34:73-80.
associated activator of morphogenesis; JNK: c-Jun N-terminal kinase.
WNT pathway regulates chondrogenesis at different stages in
different ways. Hyperexpression of WNT 4, WNT 3a and fzl 7
blocks mesenchymal condensation, whereas WNT 7a and
WNT14 hyperexpression blocks the transition from the
condensation states to the cartilaginous nodule formation
(7,84–86). Some of the WNT pathway components stimulate
the chondrogenic differentiation of mesenchymal cells. For
example, WNT5a and WNT5b induce chondrogenesis in-vitro
by stimulating cartilage nodule formation and acting on
proliferation/differentiation via the expression of cell cycle
regulators: cyclinD1 and p130 (7,87). Aberrant activation of
the WNT pathway results in squeletal malformations and
inhibition of the chondrogenesis (87).
WNT signaling during late stages of cartilage
development and adulthood
Differentiated chondrocyte can either form articular cartilage
or undergo hypertrophy and form sub-chondral bone. During
sub-chondral ossification, many WNT pathway components
are expressed and are responsible for the hypertrophic
maturation of chondrocytes (86). Furthermore, WNT5a and
WNT5b (other than stimulating early stages of chondrogen-
esis) inhibit chondrocytes hypertrophy during late stages of
development (6,7,87,88). Other data showed that chondro-
cytes hypertrophy is delayed or even blocked by sFRP1, fzl1
and fzl7 hyperexpression (86,89). Gaur et al. (2006) observed
during the post natal development in sFRP1/ mice, a
shortened height of the growth plate and increased calcifica-
tion of the hypertrophic zone suggesting endochondral
ossification. The absence of sFRP1 molecule also accelerates
terminal differentiation of hypertrophic chondrocytes (90).
On the other hand, Ladher et al. (2000) showed that WNT4
accelerates chondrocytes terminal differentiation and blocks
chondrogenesis initiation (7). Hyperexpression of WNT4 or
the b-catenin stimulate the terminal differentiation of growth
J Recept Signal Transduct Res, 2014; 34(2): 73–80
plate cartilage (76,86). However, the lack in the b-catenin
expression results in delaying the chondrocytes maturation
and the sub-chondral bone formation (91).
Depending on the stage of cartilage formation and the
molecules involved, WNT can stimulate chondrogenesis or
inhibit it. As a general rule, WNT proteins function can
drastically change temporally (during embryogenesis or in
mature tissues) or spatially (in-vivo, in-vitro, in sub-chondral
bone, at the surface of articular cartilage).
WNT signaling, experimental models and OA
Several studies were interested in the involvement of WNT
signaling in articular pathologies. Actual data are in favor of
the involvement of WNT signaling in rheumatologic diseases
(10–12,92). Only few of them studied the relation between
this pathway and OA. Most of the studies used in-vitro models
to elucidate the involvement of WNT in the physiopathology
of OA including treated cell cultures, cartilage ex-vivo
staining, etc. The aim of these studies was either to analyze
OA cartilage markers such as IL-1, collagens or the WNT
pathway components such as effector molecules (WNT5,
WNT7, co-receptor LRP, b-catenin), inhibitors (DKK, sFRP),
target genes (c-jun, cyclins).
IL-1 is a cytokine involved in cartilage destruction during
OA, it is also known as a non-specific activator of the WNT
pathway (93,94). Ryu et al. (2006) studied the effect of IL-1
on cultured rabbit chondrocytes. Their results showed that
IL-1 upregulated WNT5a expression which is associated with
cartilage destruction by inhibition of colII (95). They also
showed by immunoblot that passaged IL-1 treated rabbit
chondrocytes tend to accumulate cytoplasmic b-catenin and
that the passages resulted in the inhibition of GSK3b (the
enzyme responsible for proteosomal b-catenin degradation).
Northern blot analysis indicated that there were no changes in
b-catenin transcript levels (95). In the same context, our team
 DOI: 10.3109/10799893.2013.863919
treated passaged human chondrocytes with IL-1. This treat-
ment resulted in an accentuated fibroblast-like morphology
starting from the first passage. This dramatic change in the
morphology was followed by an extinction of colII expression
and an increase in colI and MMP13 expression (97). These
changes were concomitant with a significant increase in LRP5
expression during the passages and compared to non-treated
cultures. The results showed a significant increase in WNT5a
and b-catenin expression during the passages. On the other
hand, WNT7a decreased significantly during the passages
tending to the extinction in IL-1 treated and non-treated
cultures (97).
It is clear that WNT soluble molecules are the key
initiators of the whole WNT pathway and have distinct effects
on the downstream events. In fact, they are usually assigned
either to the WNT/b-catenin signaling or the WNT/Ca2þ/PCP
signaling, which is not yet completely elucidated.
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b-catenin, as a key effector of WNT signals, is a
‘‘kingpin’’ protein in the downstream events of WNT
signaling. However, there is a discrepancy in the literature
concerning the precise role of b-catenin during OA. On one
hand, Hwang et al. showed that b-catenin expression was
Journal of Receptors and Signal Transduction 2014.34:73-80.
higher in the most damaged zones of human OA cartilage
compared to the less damages zones. Besides, their results
using rabbit in-vitro chondrocytes culture strongly suggest
that WNT proteins may play a role in b-catenin accumulation
in OA/de-differentiated chondrocyte (93,98,99). Ryu et al.
(2002) were interested in analyzing the eventual interaction
between b-catenin and Jun gene family (known to be a
downstream of b-catenin activation). They showed that
accumulation of b-catenin during rabbit chondrocytes de-
differentiation causes increased expression of Jun protein.
Furthermore, these authors showed that the expression and
distribution pattern of b-catenin and jun is similar during
chicken chondrogenesis both in-vivo and in-vitro and
localized at different zones from those where colII is
expressed. These results confirmed that jun expression is
under the control of b-catenin during both cartilage formation
and cartilage destruction processes (96).
On the other hand, there are arguments in favor of
a protective role of WNT/b-catenin signaling during cartil-
age pathology (97,100–104). The activation of the WNT/
b-catenin signaling in mature cartilage has been shown to be
responsible for chondrocytes maturation in murin model
(89,100). Zhu et al. (2008), inhibited b-catenin expression in a
murin model and showed by histochemical staining severe
cartilage damage and increased cell apoptosis (103).
Furthermore, Dell’Accio et al. (2006) cultured human articu-
lar chondrocytes with a b-catenin activator, the qPCR results
showed a significant increase in colII and aggrecan expres-
sion (101). Moreover, in a rat model of OA, Weng et al.
(2010) used DKK1-antisense nucleotide injections and
showed by histochemistry that the treatment induced a
significant reduction of OA lesions and chondrocytes apop-
tosis (102). Weng et al. (2009), also showed, by immunohis-
tochemistry, that DKK1 levels in OA human cartilage is
significantly higher in comparison to individuals with femoral
fracture (105).
Unless the WNT pathway molecules and their roles are
completely elucidated, it is difficult to assign a precise role to
WNT signaling and chondrocytes 77
the b-catenin cascade. In this context, starting with defining
the potential roles of the WNT pathway molecules (WNT
proteins, co-receptors, etc) can help achieve this goal.
According to the literature data, the most relevant extra-
cellular proteins during OA in the WNT signaling are the
inhibitors: DKK and sFRP (26,32). They act by antagonizing
WNT protein activation of the pathway either by binding to
receptor fzl (resulting in the inhibition of all WNT cascades)
or co-receptor LRP (resulting in the inhibition of the
b-catenin cascade), respectively.
Lories et al. (2007) reported that deficient mice in sFRP
gene showed MMPs hyper-expression resulting in proteogly-
cans networks degradation (11). They suggested a protective
role played by sFRP protein. Lane et al. (2007) showed that
the levels of circulating DKK1 were inversely proportional to
the evolution of OA in a population of patients with
radiographic OA (12).
Using human model, we studied, in a previous work, the
effect of these two inhibitors on de-differentiated chondro-
cytes to characterize the specific roles for the canonical and
non-canonical signaling. The results showed that sFRP3
treatment resulted in maintaining the chondrogenic morph-
ology and the expression of colII and aggrecan. sFRP3
treatment also showed a significant decrease in eNOS in
LRP5 expression during the passages and compared to non-
treated cultures (104). These results suggest that sFRP plays
potentially a protective role during cartilage destruction
mediated by chondrocytes de-differentiation.
We also used a DKK1 treated de-differentiated human
articular chondrocytes model. The results from this study
showed a delay in the apparition of the fibroblast-like
morphology (similar to sFRP3 treated chondrocytes). That
was confirmed by the maintained expression of colII and
aggrecan and the reduction in MMP13 expression. eNOS
increased significantly under this treatment (104).
Conclusions from these studies were that WNT/b-catenin is
responsible for the inhibition of colII (catabolic effect) and
WNT7a expression. It is also possible that WNT5a regulates
eNOS expression during the de-differentiation. C-jun and
cyclin E1 were confirmed as downstream targets of WNT
signaling.
Finally, there is no doubt that the WNT pathway molecules
have to keep a certain balance to preserve joint integrity and
constant homeostasis. Upregulation of WNT7a may partici-
pate in the critical regulation of col II expression. It is
possible, that there are other WNT molecules in the WNT/
b-catenin cascade responsible of the regulation of MMP13.
However, considering an eventual cross talk between the
canonical and the non-canonical signaling and according to
the literature data, there is a possibility that MMP13 might
be regulated by WNT5a molecule. This latter might also be
responsible for enhancing eNOS expression during the de-
differentiation. The literature results confirm that c-jun is a
downstream target of WNT/b-catenin signaling. On another
hand, cyclin E1 is probably a downstream of the non-
canonical signaling. The importance of these two target genes
comes from the fact that they are significantly involved in cell
cycle and apoptotic process. Data from studies on these two
genes can clarify the relationship between WNT activation
and the physiopathology of OA including the modifications
 78 N. Sassi et al.
that the chondrocyte undergoes during the de-differentiation
process.
Conclusion
Chondrocytes de-differentiation during OA is the clue to
understand the pathology. It seems to be intimately related to
signaling pathways. There are, certainly, signaling pathways
that are involved in cell cycle and probably more involved in
‘‘pathologic cell cycle’’ (106). The future researches should
focus on characterizing the ‘‘trigger’’ in the signaling network
that leads to the turn-over in healthy cartilage proteins
expression.
The discrepancy in the literature concerning the role
played by the WNT signaling components and their assign-
ment to one cascade or to another should also be elucidated
by deeper research. A better understanding of these signaling
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cascades is necessary and may be the key to develop new
therapeutic approaches to treat OA.
Declaration of interest
The authors report no conflicts of interests. The authors alone are
Journal of Receptors and Signal Transduction 2014.34:73-80.
responsible for the content and writing of this article.
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