A role for age-related changes in TGF beta signaling in aberrant chondrocyte differentiation and osteoarthritis

Transforming growth factor beta (TGF beta) is a growth factor with many faces. In our osteoarthritis (OA) research we have found that TGF beta can be protective as well as deleterious for articular cartilage. We postulate that the dual effects of TGF beta on chondrocytes can be explained by the fact that TGF beta can signal via different receptors and related Smad signaling routes. On chondrocytes, TGF beta not only signals via the canonical type I receptor ALK5 but also via the ALK1 receptor. Notably, signaling via ALK5 (Smad2/3 route) results in markedly different chondrocyte responses than ALK1 signaling (Smad1/5/8), and we postulate that the balance between ALK5 and ALK1 expression on chondrocytes will determine the overall effect of TGF beta on these cells. Importantly, signaling via ALK1, but not ALK5, stimulates MMP-13 expression by chondrocytes. In cartilage of ageing mice and in experimental OA models we have found that the ALK1/ALK5 ratio is significantly increased, favoring TGF beta signaling via the Smad1/5/8 route, changes in chondrocyte differentiation and MMP-13 expression. Moreover, human OA cartilage showed a significant correlation between ALK1 and MMP-13 expression. In this paper we summarize concepts in OA, its link with ageing and disturbed growth factor responses, and a potential role of TGF beta signaling in OA development.