Experimental Rheumatology & Advanced Therapeutics, NCMLS, Radboud University, Medical Centre Nijmegen, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands.
Arthritis Res Ther. 2010;12(1):201. doi: 10.1186/ar2896. Epub 2010 Jan 29.
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.
转化生长因子β（TGFβ）是一种具有多种功能的生长因子。在我们的骨关节炎（OA）研究中发现，TGFβ 对关节软骨既有保护作用，也有损伤作用。我们假设 TGFβ 对软骨细胞的双重作用可以用以下事实来解释，即 TGFβ 可以通过不同的受体和相关的 Smad 信号通路进行信号传递。在软骨细胞上，TGFβ不仅通过经典的 I 型受体 ALK5 进行信号传递，还通过 ALK1 受体进行信号传递。值得注意的是，ALK5 信号传递（Smad2/3 途径）导致的软骨细胞反应与 ALK1 信号传递（Smad1/5/8）明显不同，我们假设软骨细胞上 ALK5 和 ALK1 的表达平衡将决定 TGFβ 对这些细胞的整体影响。重要的是，ALK1 信号传递而非 ALK5 信号传递会刺激软骨细胞表达 MMP-13。在衰老小鼠的软骨和实验性 OA 模型中，我们发现 ALK1/ALK5 比值显著增加，有利于 TGFβ 通过 Smad1/5/8 途径进行信号传递，改变软骨细胞分化和 MMP-13 表达。此外，人类 OA 软骨中 ALK1 和 MMP-13 的表达存在显著相关性。本文总结了 OA 的概念、与衰老的联系以及生长因子反应失调，以及 TGFβ 信号传递在 OA 发展中的潜在作用。
