Abstract

Osteoarthritis (OA) is the most common form of arthritis, and connective tissue growth factor (CTGF) is found to be up-regulated in adjacent areas of cartilage surface damage. CTGF is present in osteophytes of late stage OA. In the present study, we have reviewed association of CTGF in the development and progression of OA and the potential effects of CTGF as a therapeutic agent for the treatment of OA. We have reviewed the recent articles on CTGF and OA in databases like PubMed, google scholar, and SCOPUS and collected the information for the articles. CTGF is usually up-regulated in synovial fluid of OA that stimulates the production of inflammatory cytokines. CTGF also activates nuclear factor-κB, increases the production of chemokines and cytokines, and up-regulates matrix metalloproteinases-3 (MMP-3) that in turn leads to the reduction in proteoglycan contents in joint cartilage. Consequently, cartilage homeostasis is imbalanced that might contribute to the pathogenesis of OA by developing synovial inflammation and cartilage degradation. CTGF might serve as a useful biomarker for the prognosis and treatment of OA, and recent studies have taken attempt to use CTGF as therapeutic target of OA. However, more investigations with clinical trials are necessary to validate the possibility of use of CTGF as a biomarker in OA diagnosis and therapeutic target for OA treatment.

Introduction

Connective tissue growth factor (CTGF; also known as CCN2) is a member of the CCN (CYR61-CTGF-NOV) family, which is a group of secreted multifunctional proteins [1–3]. CTGF is known to be up-regulated in pathological conditions in regions of severe injury including fibrotic disorders, various cancers, and arthritis. CTGF has also been shown to be up-regulated adjacent to areas of cartilage surface damage, and present and in osteophytes of late stage osteoarthritis (OA) [4–6]. CTGF was first discovered by Bradham in 1991. It is a 38 kD cysteine-rich (CR) protein made up of five domains, including secretory signal peptide (SP), insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C repeat (VWC), thrombospondin type 1 repeat (TSP1), and C-terminal cystine-knot (CT) modules. The N-terminal domain of CTGF interacts with aggrecan and mediates myofibroblast differentiation and collagen synthesis. IGFBP binds IGFs with high affinity and exerts biological effects by modulating IGF behavior. VWC domains, also referred to as chordin-like CR repeats, are an extremely common motif found in extracellular matrix (ECM) proteins. TSP domain binds a wide range of extracellular targets and important signaling molecules including collagen V, fibronectin, TGF-β, and heparin. The CT domain interacts with members of the TGF-β superfamily and mediates fibroblast proliferation [7–9]. Figure 1 shows CTGF protein structure. This matricellular protein is required for the development of fibrotic tissues in a variety of organs. It is strongly expressed in growth of cartilage, especially in hypertrophic chondrocytes, and plays an essential role in endochondral ossification by promoting angiogenesis, proliferation, and differentiation of chondrocytes [10–12]. CTGF has also been played role in a diverse range of cellular functions including migration, adhesion, survival, wound healing, and synthesis of ECM proteins in various cell types. CTGF exerts its functions by binding to various cell surface receptors including integrin receptors, cell surface heparan sulfate proteoglycans (HSPGs), low density lipoprotein receptor-related protein (LRP), and the tyrosine kinase receptor (TrkA) [13]. OA is the most common form of arthritis, and a major cause of morbidity. It is a chronic joint disorder accompanied by varying degrees of functional limitation and reduced quality of life. OA is characterized by slow progressive degeneration of articular cartilage, fibrosis, subchondral bone alteration, osteophyte formation, and secondary induced synovitis [14–16]. OA becomes more frequent in both sexes amongst the older people, and is supposed to be the fourth leading cause of disability by the year 2020 [17,18]. The cause of the OA is unclear, although obesity, ageing, sex, genetic factors, biological, and biomechanical components have been associated with increased risk of OA. Numerous studies have suggested that increased production and activation of degradative enzymes, altered synthesis of cartilage matrix molecules, and growth factors are believed to play a central role in this pathological process [19,20]. The most common clinical symptoms of OA are joint pain, swelling, decreased range of motion and stiffness [21]. OA cannot be cured totally, only some management is purely supportive to control the symptoms and pain reduction. However, most of the conventional management options are not always satisfactory as these options are not readily available, expensive and have large risk of side effects [22,23]. To overcome these problems, development of new and potential alternative therapeutics is urgently needed. It is also important to know the factors that are involved in the pathophysiology of OA to identify the more effective targets for OA therapy [24–26].

CTGF protein structure

Figure 1
CTGF protein structure

CTGF have five domains, including secretory SP, IGFBP, VWC, TSP1, and C-terminal cystine-knot (CT) modules. Some of the known binding partners of each module are also listed: integrins; IGFs; bone morphogenic proteins; transforming growth factor-β (TGF-β); LRP1; VEGF; HSPGs; TrkA [7–9,13].

Figure 1
CTGF protein structure

CTGF have five domains, including secretory SP, IGFBP, VWC, TSP1, and C-terminal cystine-knot (CT) modules. Some of the known binding partners of each module are also listed: integrins; IGFs; bone morphogenic proteins; transforming growth factor-β (TGF-β); LRP1; VEGF; HSPGs; TrkA [7–9,13].

In this review, we have focussed on the association of CTGF in the development and progression of OA and the potential effects of CTGF as a therapeutic agent for the treatment of OA.

Abnormal CTGF expression in disease progression

CTGF plays an important role in many physiological and pathological activities including inflammation, wound-healing, fibrosis, angiogenesis, and carcinogenesis [11,27]. CTGF has been implicated in all fibrotic conditions and detected in joint capsule tissue or contracted joints of the synovium in hemophilia patients [1]. Some evidences identified that increased expression of CTGF could also be involved in the onset of rheumatoid arthritis by enhancing the activity of osteoclasts [9]. CTGF is normally expressed in developing tissues; however, it is reported to be the most abundantly expressed growth factor in chondrocytes of human patients with severe OA. CTGF mRNA has been found to be up-regulated adjacent to areas of cartilage surface damage and present in chondro-osteophytes [6]. CTGF expression is modulated by several factors, including transforming growth factor β (TGFβ), dexamethasone, macrophage colony stimulating factor, VEGF, prostaglandin E2 (PGE2), and retinoic acidin various cell types. CTGF is also up-regulated in response to mechanical stimuli [5,28]. In an animal model, CTGF overexpression in synovial lining of mouse knee joints induces fibrosis and cartilage damage. The cartilage damage could be either a direct effect of CTGF overexpression or a result of factors excreted by the CTGF-induced fibrotic synovial tissue [29].

Role of CTGF in OA pathogenesis

CTGF is currently an attracting attention as it has several potential functions in chondrocytes. During chondrogenesis, CTGF acts as a signal conductor in matrix remodeling and endochondral ossification by promoting angiogenesis, proliferation and chondrocyte differentiation, the expression of type II collagen, and aggrecan amongst other factors, and the activation of integrin signaling [30,31]. CTGF plays a critical role in synovial fibrosis and osteophyte formation, and has been reported to contribute to the pathogenesis of OA. Figure 2 represents the pathogenic role of CTGF in OA progression. CTGF has been found to be the most abundantly expressed growth factor in chondrocytes of human patients with severe OA [32]. CTGF can modulate the balance between synthesis and degradation of the matrix in the cartilage in inflammatory arthritis [33]. CTGF overexpression of syovium in OA patients caused by up-regulation of matrix metalloproteinase 3 (MMP-3) would reduce the content of proteoglycans in joint cartilage and result in transient fibrosis [29]. In OA knees, TGF-β stimulates CTGF expression, and is involved in joint swelling by inducing synovial cells to synthesize endogenous hyaluronan [34]. It has been demonstrated that many OA patients show a changed morphology and inflammatory phenotype in the synovial tissue characterized by hypertrophy and the infiltration of leucocytes and monocytes/macrophages. Monocyte chemoattractant protein-1 (MCP-1/CTGF) is the key chemokine that regulates migration and infiltration of monocytes, and are critical mediators of the disturbed metabolism and enhanced catabolism of joint tissue involved in OA. CTGF enhances the monocyte migration in OASFs by increasing MCP-1 expression through the αvβ5 integrin, FAK, MEK, ERK, and nuclear factor-κB (NF-κB)/AP-1 signal transduction pathway. Migration and infiltration of mononuclear cells to inflammatory sites has been reported to enhance the synovial inflammation and secreted inflammatory factors (IL-1, IL-6, IL-8, TNF-α, and PGE2) and a variety of MMP, and is thought to play a central role during OA pathogenesis [35,36]. CTGF participates in the inflammatory process in OA through NF-κB-dependent pathway. NF-κB signaling pathway constitutes a family of transcription factors that are stimulated by pro-inflammatory cytokines or ligands. NF-κB is induced by ectopic expression of Rap1 (Trf2IP, an essential modulator of NF-κB-mediated pathways) that forms a complex with IKKs. IKKs recruits to and phosphorylate the p65 subunit of NF-κB to make it transcriptionally active competent. Upon stimulation, the activated NF-κB molecules trigger the expression of target genes which induce destruction of the articular joint, leading to OA progression. WIP1 phosphatase is a negative regulator of NF-κB signaling. Overexpression of WIP1 resulted in decreased NF-κB activation, whereas WIP1 knockdown resulted in increased NF-κB function and enhanced inflammation (Figure 3) [37–39]. In addition, VEGF (a mediator of angiogenesis) acts as the potential growth factor implicated in the pathogenesis of OA. CTGF induces production of VEGF by raising miR-210 expression via PI3K, AKT, ERK, and NF-κB/ELK1 pathways, contributing to inhibit glycerol-3-phosphate dehydrogenase 1-like expression and prolyl hydroxylases-2 activity, promoting hypoxia-inducible factor-1α-dependent VEGF expression and angiogenesis in OASFs (Figure 4) [36]. Zhao et al. suggested that epigenetic changes in the methylation status of CTGF contribute to the pathology of OA. They reported that CTGF gene is hypomethylated in OA chondrocytes, and has a consistent correlation with mRNA expression [40]. CTGF promotes interleukin (IL)-1β-mediated synovial inflammation in knee OA [41]. In contrast with these studies, other experiments indicate a protective or anabolic role of CTGF in OA. CTGF is suspected to play a critical role in cartilage repair. In the MIA-induced OA model, Nishida et al. showed that the local administration of recombinant CTGF (rCTGF) into defective articular cartilage could regenerate the cartilage. They administered a single injection of rCTGF incorporated in gelatin hydrogel into the joint cavity of rats and demonstrated repair of damaged cartilage to the extent that it became histologically similar to normal articular cartilage. Therefore, CTGF expression and regulation are of particular interest [42].

The role of CTGF in OA pathogenesis

Figure 2
The role of CTGF in OA pathogenesis

The expression of CTGF is up-regulated in synovial fluid of OA and up-regulation of CTGF stimulates the production of inflammatory cytokines [32,35,36]. CTGF also activates NF-κB pathway, increases the production of chemokines and cytokines, and up-regulates MMP-3 which in turn leads to the reduction in the content of proteoglycans in joint cartilage. As a consequence, cartilage homeostasis is imbalanced that might contribute to the pathogenesis of OA by developing synovial inflammation and cartilage degradation [29,33].

Figure 2
The role of CTGF in OA pathogenesis

The expression of CTGF is up-regulated in synovial fluid of OA and up-regulation of CTGF stimulates the production of inflammatory cytokines [32,35,36]. CTGF also activates NF-κB pathway, increases the production of chemokines and cytokines, and up-regulates MMP-3 which in turn leads to the reduction in the content of proteoglycans in joint cartilage. As a consequence, cartilage homeostasis is imbalanced that might contribute to the pathogenesis of OA by developing synovial inflammation and cartilage degradation [29,33].

NF-κB signaling and its target genes

Figure 3
NF-κB signaling and its target genes

NF-κB signaling pathway constitutes a family of transcription factors that are stimulated by pro-inflammatory cytokines or ligands. The activated NF-κB molecules trigger the expression of target genes which induce destruction of the articular joint, leading to OA progression [37–39].

Figure 3
NF-κB signaling and its target genes

NF-κB signaling pathway constitutes a family of transcription factors that are stimulated by pro-inflammatory cytokines or ligands. The activated NF-κB molecules trigger the expression of target genes which induce destruction of the articular joint, leading to OA progression [37–39].

Role of CTGF in VEGF production in OA synovial fibroblasts

Figure 4
Role of CTGF in VEGF production in OA synovial fibroblasts

CTGF activates PI3K, AKT, ERK, and NF-κB pathway, inducing VEGF expression and promoting angiogenesis, proliferation and chondrocyte differentiation in human synovial fibroblasts [36].

Figure 4
Role of CTGF in VEGF production in OA synovial fibroblasts

CTGF activates PI3K, AKT, ERK, and NF-κB pathway, inducing VEGF expression and promoting angiogenesis, proliferation and chondrocyte differentiation in human synovial fibroblasts [36].

CTGF -targetted treatment approach in OA

OA is the leading cause of morbidity and the most common form of arthritis characterized by progressive degeneration of articular cartilage. The conventional therapy of OA is still unsatisfactory. The use of biochemical markers may diagnose the disease at an earlier stage, and may develop safe and effective disease modifying treatments for patients with OA. CTGF might serve as a useful biomarker for the prognosis and treatment of OA [14,43]. Table 1 and Figure 5 summarize the therapeutic use of CTGF in the treatment of OA.

Therapeutic roles of CTGF in the treatment of OA

Figure 5
Therapeutic roles of CTGF in the treatment of OA

CTGF can be a good target for the drug development to treat OA [14,43].

Figure 5
Therapeutic roles of CTGF in the treatment of OA

CTGF can be a good target for the drug development to treat OA [14,43].

Table 1
Potential therapeutic roles of CTGF in the treatment of osteoarthritis
Therapeutic agents Experimental cells/model Effects Ref 
Berberine Collagenase-induced rat model Attenuated CTGF-induced IL-1β expression and exhibited an anti-inflammatory effect [44
αvβ5 integrin neutralized antibody and ASK1 shRNA Human synovial fibroblasts Attenuated CTGF mediated IL-6 production [2
ROCK inhibitor Osteoarthritic articular chondrocytes Inhibited the cartilage degradation via TGFβ /Smad signaling [28
Antibodies against CTGF Chondrocyte cell lines Stimulated PG synthesis [45
Heterochromatin protein gamma Osteoarthritic articular chondrocytes Suppressed the expression of MMP3 [46
Harmine Human chondrocytic HCS-2/8 cells and osteoarthritic articular chondrocytes Showed chondroprotective effect [48
Thrombospondin 1 type 1 repeat module (TSP1) Osteoarthritic articular chondrocytes and rat model Induces cartilage regeneration [49
Therapeutic agents Experimental cells/model Effects Ref 
Berberine Collagenase-induced rat model Attenuated CTGF-induced IL-1β expression and exhibited an anti-inflammatory effect [44
αvβ5 integrin neutralized antibody and ASK1 shRNA Human synovial fibroblasts Attenuated CTGF mediated IL-6 production [2
ROCK inhibitor Osteoarthritic articular chondrocytes Inhibited the cartilage degradation via TGFβ /Smad signaling [28
Antibodies against CTGF Chondrocyte cell lines Stimulated PG synthesis [45
Heterochromatin protein gamma Osteoarthritic articular chondrocytes Suppressed the expression of MMP3 [46
Harmine Human chondrocytic HCS-2/8 cells and osteoarthritic articular chondrocytes Showed chondroprotective effect [48
Thrombospondin 1 type 1 repeat module (TSP1) Osteoarthritic articular chondrocytes and rat model Induces cartilage regeneration [49

A significant number of natural compounds that induce CTGF in chondrocytes could be novel candidates to correct cartilage degenerative changes in OA. Berberine has been suggested as a novel therapeutic strategy for managing OA. CTGF-induced IL-1β expression in OASFs is attenuated by the treatment with berberine. Berberine exhibits an anti-inflammatory effect which reverses cartilage damage in an experimental model of collagenase-induced OA. Berberine was found to inhibit the signaling components in OASFs in vitro and prevent cartilage degradation in vivo [44]. OASFs stimulation with CTGF induced concentration-dependent increases in IL-6 expression. CTGF mediated IL-6 production was attenuated by αvβ5 integrin neutralized antibody and apoptosis signal-regulating kinase 1 (ASK1) shRNA. The potentiating action of CTGF can also be inhibited by treating with p38 inhibitor (SB203580), JNK inhibitor (SP600125), AP-1 inhibitors (Curcumin and Tanshinone IIA), and NF-κB inhibitors (PDTC and TPCK) [2]. Woods et al. showed that CTGF is responsive to both Rac1 and actin pathways in chondrocytes which might be relevant to OA. They suggested that CTGF expression might be controlled by either inhibition of actin polymerization (cytochalasin D treatment), promotion of actin polymerization (jasplakinolide treatment), inhibition of RhoA/rho kinase (ROCK) signaling (Y27632 treatment), and Rac1 signaling [28]. CTGF is involved in inhibition of PG synthesis. Minato et al. established three different antibodies against CTGF that stimulated PG synthesis in chondrocyte cell lines [45]. Masuko et al. obtained articular cartilage samples from OA patients and chondrocytes were isolated and cultured in vitro. They stimulated chondrocytes with PGE2, PGE receptor (EP)-specific agonists/IL-1. They showed that stimulation of chondrocytes with PGE2 or IL-1 significantly suppressed CTGF expression [5].

Matrix metalloproteinase 3 (MMP3) is well known as a secretory endopeptidase that also acts as a trans regulator of CTGF. CTGF is activated by overexpressed MMP3 and knocking down of MMP3 suppressed CTGF expression [46]. Eguchi et al. suggested that the role of MMP3 in the development, tissue remodeling, and pathology of arthritic diseases can be regulated through CTGF. They determined that heterochromatin protein γ coordinately regulates CTGF by interacting with MMP3. The potentially therapeutic effect of intact CTGF on cartilage regeneration has been indicated by a number of studies [46]. In a study, Tang et al. determined the function of CTGF in OA development. They generated a postnatal, conditional CtgfcKO mouse for cartilage injury experiments and to explore the course of OA. They reported that deletion of CTGF in vivo increased the thickness of the articular cartilage and protected mice from OA through TGF-β-dependent SMAD2 phosphorylation [47].

In contrary, there are evidences that CTGF inducer may also have beneficial effects on OA treatment. Hara et al. suggested that a significant number of natural compounds that induce CTGF in chondrocytes could be novel candidates to correct cartilage degenerative changes incurred in OA. They identified the β-carboline alkaloid harmine as a novel inducer of CTGF in human chondrocytic HCS-2/8 cells and osteoarthritic articular chondrocytes. The chondroprotective effect of harmine was investigated by stimulation with TNFα, and it was shown to ameliorate TNFα-induced decrease in expression of CTGF and cartilage markers aggrecan, SOX-9 and COL2α1 [48]. Abd El Kader et al. suggested thrombospondin 1 type 1 repeat module (TSP1) as a promising regenerative therapeutics of OA. Their study showed that TSP1 displayed more prominent regenerative effects than intact CTGF on damaged cartilage [49]. There is a lack of evidence that may support that reducing the expression of CTGF is a successful strategy in OA treatment. More investigations are necessary to check the performance of CTGF in a specific cohort of patients with earlier stage. It is also essential to define the signaling events induced by CTGF for the inhibition of CTGF-mediated inflammatory process.

Inhibitors of NF-κB pathway signaling might be used for a variety of autoimmune and inflammatory disorders. Ikk2 (IκB kinase) is a component of NF-κB pathway that is important drug target both in inflammation and cancer. Ikk2 coordinates the cellular response to a diverse set of extracellular stimuli. In response to an external stimulus, Ikk2 induces NF-κB transcription factor, which activates the transcription of genes that regulate a variety of fundamental biological processes. Targetting this kinase by inhibitors may underscore the potential for therapeutic intervention. VEGFR inhibitors might also be used for treating inflammation and cancer by targetting anti-angiogenic mediators. γ-tocotrienol (a vitamin E derivative derived from palm oil) inhibited VEGF- induced migration, invasion, tube formation and viability of HUVECs in vitro as well as reduced the blood vessels formation. γ-tocotrienol was also found to inhibit angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Noncoding RNAs (ncRNA) might play an important role in the regulation of inflammatory signaling. The use of ncRNA may open new avenues for the potential therapeutic intervention in inflammatory diseases, from arthritis to cancer, which may be translated into clinical outcomes in the future [50–52].

Conclusion

OA is becoming a big threat for normal healthy life. Early diagnosis and administration of effective treatment may be the best strategies against OA. Recent studies have taken attempt to use CTGF as a diagnostic marker for OA to evaluate its treatment effects. More investigations with clinical trials are necessary to validate the possibility of use of CTGF as a biomarker in OA diagnosis. The use of CTGF-antagonists can be a good candidate for the drug development to treat OA in near future. The better understanding of the role of CTGF in OA may provide a basis for new therapeutic approaches to treat OA.

Funding

This work was supported by the Provincial Science Foundation of Hubei [grant number 2016cfb110].

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • CR

    cysteine-rich

  •  
  • CTGF

    connective tissue growth factor

  •  
  • ECM

    extracellular matrix

  •  
  • HSPG

    heparan sulfate proteoglycan

  •  
  • IGFBP

    insulin-like growth factor binding protein

  •  
  • IGF

    insulin-like growth factor

  •  
  • IL

    interleukin

  •  
  • LRP1

    lipoprotein receptor-related protein1

  •  
  • MCP-1

    monocyte chemoattractant protein-1

  •  
  • MCSF

    macrophage colony stimulating factor

  •  
  • MMP

    matrix metalloproteinases

  •  
  • NF

    nuclear factor

  •  
  • OA

    osteoarthritis

  •  
  • PGE2

    prostaglandin E2

  •  
  • SP

    signal peptide

  •  
  • TSP1

    thrombospondin type 1 repeat

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • VWC

    von Willebrand factor type C

References

References
1.
Jiang
J.
,
Leong
N.L.
,
Khalique
U.
,
Phan
T.M.
,
Lyons
K.M.
and
Luck
J.V.
Jr
(
2016
)
Connective tissue growth factor (CTGF/CCN2) in haemophilicarthropathy and arthrofibrosis: a histological analysis
.
Haemophilia
22
,
e527
36
[PubMed]
2.
Liu
S.C.
,
Hsu
C.J.
,
Chen
H.T.
,
Tsou
H.K.
,
Chuang
S.M.
and
Tang
C.H.
(
2015
)
Correction: CTGF Increases IL-6 expression in human synovial fibroblasts through integrin-dependent signaling pathway
.
PLoS ONE
10
,
e0144569
[PubMed]
3.
Itoh
S.
,
Hattori
T.
,
Tomita
N.
,
Aoyama
E.
,
Yutani
Y.
,
Yamashiro
T.
et al.
(
2013
)
CCN family member 2/connective tissue growth factor (CCN2/CTGF) has anti-aging effects that protect articular cartilage from age-related degenerative changes
.
PLoS ONE
8
,
e71156
[PubMed]
4.
Liu
S.C.
,
Hsu
C.J.
,
Fong
Y.C.
,
Chuang
S.M.
and
Tang
C.H.
(
2013
)
CTGF induces monocyte chemoattractant protein-1 expression to enhance monocyte migration in human synovial fibroblasts
.
Biochim. Biophys. Acta
1833
,
1114
1124
[PubMed]
5.
Masuko
K.
,
Murata
M.
,
Yudoh
K.
,
Shimizu
H.
,
Beppu
M.
,
Nakamura
H.
et al.
(
2010
)
Prostaglandin E2 regulates the expression of connective tissue growth factor (CTGF/CCN2) in human osteoarthritic chondrocytes via the EP4 receptor
.
BMC Res. Notes
3
,
5
[PubMed]
6.
Omoto
S.
,
Nishida
K.
,
Yamaai
Y.
,
Shibahara
M.
,
Nishida
T.
,
Doi
T.
et al.
(
2004
)
Expression and localization of connective tissue growth factor (CTGF/Hcs24/CCN2) in osteoarthritic cartilage
.
Osteoarthritis Cartilage
12
,
771
778
[PubMed]
7.
Bradham
D.M.
,
Igarashi
A.
,
Potter
R.L.
and
Grotendorst
G.R.
(
1991
)
Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10
.
J. Cell Biol.
114
,
1285
1294
[PubMed]
8.
Kubota
S.
and
Takigawa
M.
(
2011
)
The role of CCN2 in cartilage and bone development
.
J. Cell Commun. Signal.
5
,
209
217
[PubMed]
9.
Yang
X.
,
Lin
K.
,
Ni
S.
,
Wang
J.
,
Tian
Q.
,
Chen
H.
et al.
(
2017
)
Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis
.
Arthritis Res. Ther.
19
,
257
[PubMed]
10.
Takigawa
M.
,
Nakanishi
T.
,
Kubota
S.
and
Nishida
T.
(
2003
)
Role of CTGF/HCS24/ecogenin in skeletal growth control
.
J. Cell. Physiol.
194
,
256
266
[PubMed]
11.
Kubota
S.
and
Takigawa
M.
(
2015
)
Correction: Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions
.
Clin. Sci.
129
,
674
[PubMed]
12.
Fujisawa
T.
,
Hattori
T.
,
Ono
M.
,
Uehara
J.
,
Kubota
S.
,
Kuboki
T.
et al.
(
2008
)
CCN family 2/connective tissue growth factor (CCN2/CTGF) stimulates proliferation and differentiation of auricular chondrocytes
.
Osteoarthritis Cartilage
16
,
787
795
[PubMed]
13.
Wahab
N.A.
,
Weston
B.S.
and
Mason
R.M.
(
2005
)
Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA
.
J. Am. Soc. Nephrol.
16
,
340
351
[PubMed]
14.
Hayami
T.
,
Pickarski
M.
,
Zhuo
Y.
,
Wesolowski
G.A.
,
Rodan
G.A.
and
Duong
L.T.
(
2006
)
Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis
.
Bone
38
,
234
243
[PubMed]
15.
Leung
G.J.
,
Rainsford
K.D.
and
Kean
W.F.
(
2014
)
Osteoarthritis of the hand I: aetiology and pathogenesis, risk factors, investigation and diagnosis
.
J. Pharm. Pharmacol.
66
,
339
346
[PubMed]
16.
Lajeunesse
D.
,
Massicotte
F.
,
Pelletier
J.P.
and
Martel-Pelletier
J.
(
2003
)
Subchondral bone sclerosis in osteoarthritis: not just an innocent bystander
.
Mod. Rheumatol.
13
,
7
14
[PubMed]
17.
Peat
G.
,
McCarney
R.
and
Croft
P.
(
2001
)
Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care
.
Ann. Rheum. Dis.
60
,
91
97
[PubMed]
18.
Woolf
A.D.
and
Pfleger
B.
(
2003
)
Burden of major musculoskeletal conditions
.
Bull. World Health Organ.
81
,
646
656
[PubMed]
19.
Sutton
S.
,
Clutterbuck
A.
,
Harris
P.
,
Gent
T.
,
Freeman
S.
,
Foster
N.
et al.
(
2009
)
The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis
.
Vet. J.
179
,
10
24
[PubMed]
20.
van den Berg
W.B.
,
van der Kraan
P.M.
,
Scharstuhl
A.
and
van Beuningen
H.M.
(
2001
)
Growth factors and cartilage repair
.
Clin. Orthop. Relat. Res.
391
,
S244
50
21.
Wieland
H.A.
,
Michaelis
M.
,
Kirschbaum
B.J.
and
Rudolphi
K.A.
(
2005
)
Osteoarthritis – an untreatable disease?
Nat. Rev. Drug Discov.
4
,
331
344
,
Review. Erratum in: Nat Rev Drug Discov. 2005;4:543
[PubMed]
22.
Vargas Negrín
F.
,
Medina Abellán
M.D.
,
Hermosa Hernán
J.C.
and
de Felipe Medina
R.
(
2014
)
Treatment of patients with osteoarthritis
.
Aten. Primaria
46
,
39
61
[PubMed]
23.
Tonge
D.P.
,
Pearson
M.J.
and
Jones
S.W.
(
2014
)
The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics
.
Osteoarthritis Cartilage
22
,
609
621
[PubMed]
24.
Felson
D.T.
(
2009
)
Developments in the clinical understanding of osteoarthritis
.
Arthritis Res. Ther.
11
,
203
[PubMed]
25.
Fajardo
M.
and
Di Cesare
P.E.
(
2005
)
Disease-modifying therapies for osteoarthritis: current status
.
Drugs Aging
22
,
141
161
[PubMed]
26.
Clouet
J.
,
Vinatier
C.
,
Merceron
C.
,
Pot-vaucel
M.
,
Maugars
Y.
,
Weiss
P.
et al.
(
2009
)
From osteoarthritis treatments to future regenerative therapies for cartilage
.
Drug Discov. Today
14
,
913
925
[PubMed]
27.
Klaassen
I.
,
van Geest
R.J.
,
Kuiper
E.J.
,
van Noorden
C.J.
and
Schlingemann
R.O.
(
2015
)
The role of CTGF in diabetic retinopathy
.
Exp. Eye Res.
133
,
37
48
[PubMed]
28.
Woods
A.
,
Pala
D.
,
Kennedy
L.
,
McLean
S.
,
Rockel
J.S.
,
Wang
G.
et al.
(
2009
)
Rac1 signaling regulates CTGF/CCN2 gene expression via TGFbeta/Smad signaling in chondrocytes
.
Osteoarthritis Cartilage
17
,
406
413
[PubMed]
29.
Blaney Davidson
E.N.
,
Vitters
E.L.
,
Mooren
F.M.
,
Oliver
N.
,
Berg
W.B.
and
van der Kraan
P.M.
(
2006
)
Connective tissue growth factor/CCN2 overexpression in mouse synovial lining results in transient fibrosis and cartilage damage
.
Arthritis Rheum.
54
,
1653
1661
[PubMed]
30.
Leask
A.
and
Abraham
D.J.
(
2006
)
All in the CCN family: essential matricellular signaling modulators emerge from the bunker
.
J. Cell Sci.
119
,
4803
4810
[PubMed]
31.
Nishida
T.
,
Kawaki
H.
,
Baxter
R.M.
,
Deyoung
R.A.
,
Takigawa
M.
and
Lyons
K.M.
(
2007
)
CCN2 (Connective Tissue Growth Factor) is essential for extracellular matrix production and integrin signaling in chondrocytes
.
J. Cell Commun. Signal.
1
,
45
58
[PubMed]
32.
Zhang
H.
,
Liew
C.C.
and
Marshall
K.W.
(
2002
)
Microarray analysis reveals the involvement of β-2 microglobulin (B2M) in human osteoarthritis
.
Osteoarthritis Cartilage
10
,
950
960
[PubMed]
33.
Shi-Wen
X.
,
Leask
A.
and
Abraham
D.
(
2008
)
Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis
.
Cytokine Growth Factor Rev.
19
,
133
144
[PubMed]
34.
Lee
Y.T.
,
Shao
H.J.
,
Wang
J.H.
,
Liu
H.C.
,
Hou
S.M.
and
Young
T.H.
(
2010
)
Hyaluronic acid modulates gene expression of connective tissue growth factor (CTGF), transforming growth factor-beta1 (TGF-beta1), and vascular endothelial growth factor (VEGF) in human fibroblast-like synovial cells from advanced-stage osteoarthritis in vitro
.
J. Orthop. Res.
28
,
492
496
[PubMed]
35.
Haywood
L.
,
McWilliams
D.F.
,
Pearson
C.I.
,
Gill
S.E.
,
Ganesan
A.
,
Wilson
D.
et al.
(
2003
)
Inflammation and angiogenesis in osteoarthritis
.
Arthritis Rheum.
48
,
2173
2177
[PubMed]
36.
Liu
S.C.
,
Chuang
S.M.
,
Hsu
C.J.
,
Tsai
C.H.
,
Wang
S.W.
and
Tang
C.H.
(
2014
)
CTGF increases vascular endothelial growth factor-dependent angiogenesis in human synovial fibroblasts by increasing miR-210 expression
.
Cell Death Dis.
5
,
e1485
[PubMed]
37.
Teo
H.
,
Ghosh
S.
,
Luesch
H.
,
Ghosh
A.
,
Wong
E.T.
,
Malik
N.
et al.
(
2010
)
Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression
.
Nat. Cell Biol.
12
,
758
767
[PubMed]
38.
Chew
J.
,
Biswas
S.
,
Shreeram
S.
,
Humaidi
M.
,
Wong
E.T.
,
Dhillion
M.K.
et al.
(
2009
)
WIP1 phosphatase is a negative regulator of NF-kappaB signaling
.
Nat. Cell Biol.
11
,
659
666
[PubMed]
39.
Rigoglou
S.
and
Papavassiliou
A.G.
(
2013
)
The NF-κB signaling pathway in osteoarthritis
.
Int. J. Biochem. Cell Biol.
45
,
2580
2584
[PubMed]
40.
Zhao
L.
,
Wang
Q.
,
Zhang
C.
and
Huang
C.
(
2017
)
Genome-wide DNA methylation analysis of articular chondrocytes identifies TRAF1, CTGF, and CX3CL1 genes as hypomethylated in osteoarthritis
.
Clin. Rheumatol.
36
,
2335
2342
[PubMed]
41.
Wang
Z.
,
Qiu
Y.
,
Lu
J.
and
Wu
N.
(
2013
)
Connective tissue growth factor promotes interleukin-1β-mediated synovial inflammation in knee osteoarthritis
.
Mol. Med. Rep.
8
,
877
882
[PubMed]
42.
Nishida
T.
,
Kubota
S.
,
Kojima
S.
,
Kuboki
T.
,
Nakao
K.
,
Kushibiki
T.
et al.
(
2004
)
Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor)
.
J. Bone Miner. Res.
19
,
1308
1319
[PubMed]
43.
Cheng
C.
,
Zhang
F.J.
,
Tian
J.
,
Tu
M.
,
Xiong
Y.L.
,
Luo
W.
et al.
(
2015
)
Osteopontin inhibits HIF-2α mRNA expression in osteoarthritic chondrocytes
.
Exp. Ther. Med.
9
,
2415
2419
[PubMed]
44.
Liu
S.C.
,
Lee
H.P.
,
Hung
C.Y.
,
Tsai
C.H.
,
Li
T.M.
and
Tang
C.H.
(
2015
)
Berberine attenuates CCN2-induced IL-1β expression and prevents cartilage degradation in a rat model of osteoarthritis
.
Toxicol. Appl. Pharmacol.
289
,
20
29
[PubMed]
45.
Minato
M.
,
Kubota
S.
,
Kawaki
H.
,
Nishida
T.
,
Miyauchi
A.
,
Hanagata
H.
et al.
(
2004
)
Module-specific antibodies against human connective tissue growth factor: utility for structural and functional analysis of the factor as related to chondrocytes
.
J. Biochem.
135
,
347
354
[PubMed]
46.
Eguchi
T.
,
Kubota
S.
,
Kawata
K.
,
Mukudai
Y.
,
Uehara
J.
,
Ohgawara
T.
et al.
(
2008
)
Novel transcription-factor-like function of human matrix metalloproteinase 3 regulating the CTGF/CCN2 gene
.
Mol. Cell. Biol.
28
,
2391
2413
[PubMed]
47.
Tang
X.
,
Muhammad
H.
,
McLean
C.
,
Miotla-Zarebska
J.
,
Fleming
J.
,
Didangelos
A.
et al.
(
2018
)
Connective tissue growth factor contributes to joint homeostasis and osteoarthritis severity by controlling the matrix sequestration and activation of latent TGFβ
.
Ann. Rheum. Dis.
77
,
1372
1380
[PubMed]
48.
Hara
E.S.
,
Ono
M.
,
Kubota
S.
,
Sonoyama
W.
,
Oida
Y.
,
Hattori
T.
et al.
(
2013
)
Novel chondrogenic and chondroprotective effects of the natural compound harmine
.
Biochimie
95
,
374
381
[PubMed]
49.
Abd El Kader
T.
,
Kubota
S.
,
Nishida
T.
,
Hattori
T.
,
Aoyama
E.
,
Janune
D.
et al.
(
2014
)
The regenerative effects of CCN2 independent modules on chondrocytes in vitro and osteoarthritis models in vivo
.
Bone
59
,
180
188
[PubMed]
50.
Irelan
J.T.
,
Murphy
T.J.
,
DeJesus
P.D.
,
Teo
H.
,
Xu
D.
,
Gomez-Ferreria
M.A.
et al.
(
2007
)
A role for IkappaB kinase 2 in bipolar spindle assembly
.
Proc. Natl Acad. Sci. U.S.A.
104
,
16940
16945
[PubMed]
51.
Siveen
K.S.
,
Ahn
K.S.
,
Ong
T.H.
,
Shanmugam
M.K.
,
Li
F.
,
Yap
W.N.
et al.
(
2014
)
Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model
.
Oncotarget
5
,
1897
1911
[PubMed]
52.
Chew
C.L.
,
Conos
S.A.
,
Unal
B.
and
Tergaonkar
V.
(
2018
)
Noncoding RNAs: master regulators of inflammatory signaling
.
Trends Mol. Med.
24
,
66
84
[PubMed]

Author notes

*

These two authors have equal contribution.

This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).