**Author details**

growth and loss of angiogenesis [283,284] and causes death immediately after birth due to respiratory failure [239]. CCN2 binds several growth factors, including bone morphogenetic

Addition of CCN2 to damaged cartilage in rats can cause enhanced healing [263]. Although exogenous administration of matrix metalloproteases can cause damage to cartilage similar to osteoarthritis [285,286], the use of these inhibitors does not aid in the treatment of the disease [287]. Overexpression of CCN2 using a col2a1 promoter caused reversal of some aging‐related changes present in the articular cartilage of aged mice by enhancing matrix deposition and proliferation of chondrocytes. In addition, changes characteristic of cartilage degeneration were reversed, such as the expression of collagens I or X and the presence of MMPs 9 and 13 [288]. These mice also showed greater levels of matrix and faster ossification during endo‐

CCN2 binds to receptor activator of NF‐kappa B (RANK) as seen by plasmon resonance analysis, and enhances RANK signaling. This indicates its importance in the formation of

Fibroblast growth factor causes an increase in BMPs, and this binding causes repair of articular cartilage defects. Different BMPs have differing effects on this repair, but overall BMP3 is an

CCN3 decreases proliferation in several different cell types [290]. CCN3 appears to be downregulated by PTHrP [231], which is involved in the growth of bone. CCN3 may regulate apoptosis under conditions of serum deprivation. The presence of this CCN decreased levels of both proteoglycan and collagen, which may mimic the cartilage environment in which no vascularization occurs and thus conditions are somewhat hypoxic [291]. Bone regeneration in mice that lack CCN3 is enhanced [292]. Loss of CCN2 causes an increase in the expression of CCN3 with a concomitant decrease in proliferation due to the presence of this matricellular protein. This deletion also caused reduced differentiation of chondrocytes due to the upregu‐ lation of CCN3 [231]. Loss of CCN2 causes reductions in aggrecan and types II and X collagen during development, a process which mimics the matrix loss that occurs with aging during osteoarthritis development [226]. Overexpression of CCN2 has effects that counter these reductions [288]. Overexpression of CCN4 caused an effect on cartilage differentiation by changing the function of another growth factor, TGF‐β3. Mice that completely lacked CCN4 did repair surgical defects well, while mice that expressed CCN4 demonstrated some recovery from this injury [293]. Lack of another member of the CCN family, CCN6, causes a disease in humans that is a form of childhood arthritis, progressive pseudorheumatoid dysplasia [294]. The function of CCN6 in normal cartilage is not well understood, although its expression is

CCN1 and CCN2 expression is elevated during fracture repair in the long bones throughout the reparative phase of the callus, notably in proliferating chondrocytes and osteoblasts [296,297]. Abrogation of CCN1 by antibodies inhibits bone fracture healing in mice [298]. Further, recombinant CCN2 protein promotes the repair of articular cartilage in a rat osteoar‐

proteins and TGF‐β, and can affect cartilage function in this manner [226].

182 Composition and Function of the Extracellular Matrix in the Human Body

important component during repair of articular cartilage [279].

chondral bone growth [237].

high in osteoarthritis [295].

osteoclasts [289].

John A. Arnott, Kathleen Doane and Sonia Lobo Planey\*

\*Address all correspondence to: splaney@tcmc.edu

The Commonwealth Medical College, Scranton, Pennsylvania
