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

Abstract

Transforming growth factor beta (TGFbeta) is a growth factor with many faces. In our osteoarthritis (OA) research we have found that TGFbeta can be protective as well as deleterious for articular cartilage. We postulate that the dual effects of TGFbeta on chondrocytes can be explained by the fact that TGFbeta can signal via different receptors and related Smad signaling routes. On chondrocytes, TGFbeta 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 TGFbeta 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 TGFbeta 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 TGFbeta signaling in OA development.

Figure 1

Alterations in transforming growth factor beta signaling cause changes in chondrocyte differentiation and osteoarthritis development. Transforming growth factor beta (TGFβ) can either signal by the Smad2/3 route (canonical) or the Smad1/5/8 route. Smad2/3 and Smad1/5/8 form a complex with Smad4 that enters the nucleus and modulates gene expression and Runx2 function. The signaling by Smad2/3 and Smad1/5/8 is differentially modified by a number of intracellular molecules. Both Smad routes are blocked by Smad7, while Smad6 blocks preferentially the Smad1/5/8 pathway [100,101]. wnt signaling modifies these pathways by stabilization of Smad1/5/8 [102]. Smurf1 and Smurf2 are E3 ubiquitin ligases that inhibit Smad signaling. Smurf1 triggers the degradation of Smad1/5/8 while Smurf2 stimulates mainly the degradation of Smad2/3 [103]. Mitogen-activated protein kinases (MAPKs) modulate the stability and degradation of the Smads by phosphorylation of these molecules [102].