**3.4 Connective tissue growth factor**

Connective tissue growth factor (CTGF) is an ECM-associated heparin-binding protein, which plays an important role in cellular proliferation, migration, adhesion, survival and synthesis of ECM proteins. CTGF has shown to play an important role in skeletal tissue and initial chondrocyte proliferation and differentiation in growth plate cartilage [35]. Nishida and colleagues demonstrated that local

administration of recombinant CTGF gelatin hydrogel stimulated cartilage repair in rat model [36]. Other studies showed that the bone marrow-derived mesenchymal stem cells when transfected with CTGF provided hyaline-like cartilage regeneration similar to normal cartilage in a rabbit model of focal articular cartilage defects [37]. However, further studies are needed to elucidate the critical role of CTGF for the protection and regeneration of cartilage.

## **3.5 Insulin-like growth factor (IGF)**

IGF-I and IGF-II both were reported to control the cartilage destruction [38]. IGF-I is a known anabolic factor for chondrocytes and thought to regulate the skeletal development in the embryo [39]. Although IGF-I has been reported as being involved in chondrocyte proliferation and maturation, its exact role in OA has not been clearly known as it was found that the expression of IGF-I was upregulated rather than downregulated in synovial fluids and in articular cartilage [40]. However, the role of IGF-II in combating inflammatory response in OA was found to be more promising and ideal for cartilage regeneration. It has been reported that in the presence of IL-1β, IGF-II significantly inhibited MMP expression and promoted cartilage production in normal human chondrocytes. IGF-II has also shown to have a similar effect on OA chondrocyte, which expresses high levels of IL-1β mRNA [41]. The role of IGF-II was reported to be more chondroprotective and maintaining the extracellular matrix and preventing its destruction in adverse conditions.
