Expression of TGFbeta-family signalling components in ageing cartilage: age-related loss of TGFbeta and BMP receptors

Abstract

OBJECTIVE: Ageing is the main risk factor for osteoarthritis (OA). We investigated if expression of transforming growth factor beta (TGFbeta)-family components, a family which is crucial for the maintenance of healthy articular cartilage, is altered during ageing in cartilage. Moreover, we investigated the functional significance of selected age-related changes. DESIGN: Age-related changes in expression of TGFbeta-family members were analysed by quantitative PCR in healthy articular cartilage obtained from 42 cows (age: (3/4)-10 years). To obtain functional insight of selected changes, cartilage explants were stimulated with TGFbeta1 or bone morphogenetic protein (BMP) 9, and TGFbeta1 and BMP response genes were measured. RESULTS: Age-related cartilage thinning and loss of collagen type 2a1 expression ( approximately 256-fold) was observed, validating our data set for studying ageing in cartilage. Expression of the TGFbeta-family type I receptors; bAlk2, bAlk3, bAlk4 and bAlk5 dropped significantly with advancing age, whereas bAlk1 expression did not. Of the type II receptors, expression of bBmpr2 decreased significantly. Type III receptor expression was unaffected by ageing. Expression of the ligands bTgfb1 and bGdf5 also decreased with age. In explants, an age-related decrease in TGFbeta1-response was observed for the pSmad3-dependent gene bSerpine1 (P = 0.016). In contrast, ageing did not affect BMP9 signalling, an Alk1 ligand, as measured by expression of the pSmad1/5 dependent gene bId1. CONCLUSIONS: Ageing negatively affects both the TGFbeta-ALK5 and BMP-BMPR signalling routes, and aged chondrocytes display a lowered pSmad3-dependent response to TGFbeta1. Because pSmad3 signalling is essential for cartilage homeostasis, we propose that this change contributes to OA development.