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

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• 作者：A. van Caam^&dagger ; ; W. Madej^&dagger ; ; ^&Dagger ; ; E. Thijssen^&dagger ; ; A. Garcia de Vinuesa^§ ; ; W. van den Berg^&dagger ; ; M.-J. Goumans^§ ; ; P. ten Dijke^§ ; ; E. Blaney Davidson^&dagger ; ; P.M. van der Kraan^&dagger ; ; ^{Peter.vanderkraan@radboudumc.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ageing ; TGFβ receptors ; BMP receptors ; Cartilage ; Smad
• 刊名：Osteoarthritis and Cartilage
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：24
• 期：7
• 页码：1235-1245
• 全文大小：1943 K

文摘

Ageing is the main risk factor for osteoarthritis (OA). We investigated if expression of transforming growth factor β (TGFβ)-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 TGFβ-family members were analysed by quantitative PCR in healthy articular cartilage obtained from 42 cows (age: ¾–10 years). To obtain functional insight of selected changes, cartilage explants were stimulated with TGFβ1 or bone morphogenetic protein (BMP) 9, and TGFβ1 and BMP response genes were measured.

Results

Age-related cartilage thinning and loss of collagen type 2a1 expression (∼256-fold) was observed, validating our data set for studying ageing in cartilage. Expression of the TGFβ-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 TGFβ1-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 TGFβ-ALK5 and BMP-BMPR signalling routes, and aged chondrocytes display a lowered pSmad3-dependent response to TGFβ1. Because pSmad3 signalling is essential for cartilage homeostasis, we propose that this change contributes to OA development.