Transforming growth factor beta superfamily members: Role in cartilage modeling

Normal and abnormal extracellular matrix turnover is thought to result, in part, from the balance in the expression of metalloproteinases and tissue i nhibitors of metalloproteinases (TIMPs). The clinical manifestations of an imbalance in these relationships are evident in a variety of pathologic sta tes, including osteoarthritis, deficient long-bone growth, rheumatoid arthr itis, tumor invasion, and inadequate cartilage repair. Articular cartilage defects commonly heal as fibrocartilage, which is structurally inferior to the normal hyaline architecture of articular cartilage. Transforming growth factor-beta 1 (TGF-beta(1)), a cytokine central to growth, repair, and inf lammation, has been shown to up regulate TIMP-1 expression in human and bov ine articular cartilage. Additionally, members of the TGF-beta superfamily are thought to play key roles in chondrocyte growth and differentiation. Bo ne morphogenetic protein-2 (BMP-2), a member of this superfamily, has been shown to regulate chondrocyte differentiation states and extracellular matr ix composition. It was proposed that, by optimizing extracellular matrix co mposition, BMP-2 would enhance articular cartilage healing. After determini ng the release kinetics of BMP-2 from a collagen type I implant (Long-Evans male rats; two implants/rat, n = 14), it was found that, in a tissue engin eering application, BMP-2 induced a hyaline-like repair of New Zealand Whit e rabbit knee articular cartilage defects (3mm full-thickness defects in th e femoral trochlea; 2 defects/rabbit, n = 36). The quality of cartilage rep air with BMP-2 (with or without chondrocytes) was significantly better than defects treated with BMP-2, as assessed by a quantitative scoring scale. I mmunohistochemical staining revealed TIMP-1 production in the cartilage def ects treated with BMP-2. When studied in vitro, it was found that BMP-2 mar kedly increased TIMP-1 mRNA by both bovine articular and human rib chondroc ytes. Additionally, increased TIMP-1 mRNA was translated into increased TIM P-1 protein production by bovine chondrocytes. Taken together, these data s uggest that BMP-2 may be a useful cytokine to improve healing of cartilagin ous defects. Furthermore, these data suggest that the beneficial effects of BMP-2 may be, in part, related to alterations in extracellular matrix turn over.