Age-related alterations in TGF beta signaling as a causal factor of cartilage degeneration in osteoarthritis
Age-related alterations in TGF beta signaling as a causal factor of cartilage degeneration in osteoarthritis
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DOI：
10.3233/bme-140976
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发表时间：
2014-01-01
影响因子：
1
通讯作者：
van der Kraan, Peter M.
中科院分区：
文献类型：
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作者：
van der Kraan, Peter M.
背景：年龄是原发性骨关节炎（OA）最重要的危险因素。TGF-β超家族成员在软骨细胞分化和维持健康关节软骨中起着至关重要的作用。目的：我们已经调查了是否与年龄相关的变化，TGF-β超家族信号成分发挥作用，OA相关的软骨退化和aging.MATERIAL和方法之间的关系：年龄，OA和TGF-β超家族信号之间的关系进行了研究，使用小鼠实验OA模型，衰老小鼠，牛关节软骨和人OA软骨。通过免疫组化、Q-RT-PCR、Western blotting信号通路分析和特异性TGF-β抑制剂的应用研究TGF-β对软骨稳态的影响。此外，我们发现，在软骨细胞上，TGF-β不仅通过典型的I型受体ALK 5（TGFBR 1）发出信号，还通过ALK 1（ACVRL 1）受体发出信号。值得注意的是，通过ALK 5（Smad 2/3途径）的信号传导导致保护性，而ALK 1信号传导（Smad 1/5/8途径）导致关节软骨细胞中的有害反应。在衰老小鼠的软骨中，检测到ALK 1/ALK 5比率显著增加，有利于TGF-β通过Smad 1/5/8途径的信号传导，诱导软骨细胞分化和基质金属蛋白酶-13（MMP-13）表达的变化。此外，人OA软骨显示ALK 1和MMP-13表达之间的显著相关性。由于在小鼠中，衰老和OA通常是齐头并进的，我们还分析了6个月至14岁年龄范围内健康牛软骨中TGF-β超家族相关信号分子的年龄相关表达。在这个队列的老化软骨，我们发现，主要信号受体决定Smad 2/3途径随着年龄的增长而减少，而Smad 1/5/8相关的信号分子没有改变，证实了我们的研究结果在老龄化mice.CONCLUSIONS：老软骨似乎是不太保护TGF-β和TGF-β信号通路的显着改变。衰老过程中Smad 2/3通路的保护性缺失可以解释OA与衰老之间的关系。
BACKGROUND: Age is the most important risk factor for primary osteoarthritis (OA). Members of the TGF-beta superfamily play a crucial role in chondrocyte differentiation and maintenance of healthy articular cartilage. OBJECTIVE: We have investigated whether age-related changes in TGF-beta superfamily signaling components play a role in the relationship between OA-related cartilage degradation and aging.MATERIAL AND METHODS: The relationship between age, OA and TGF-beta superfamily signaling was studied using murine experimental OA models, aging mice, bovine articular cartilage and human OA cartilage. The effects of TGF-beta on cartilage homeostasis was studied with immunohistochemistry, Q-RT-PCR and signaling pathway analysis with Western blotting and the application of specific TGF-beta inhibitors.RESULTS: We have found that TGF-beta loses its protective effects in old cartilage. Moreover, we found that on chondrocytes, TGF-beta not only signals via the canonical type I receptor ALK5 (TGFBR1) but also via the ALK1 (ACVRL1) receptor. Remarkably, signaling via ALK5 (Smad2/3 route) results in protective while ALK1 signaling (Smad1/5/8 route) results in deleterious responses in articular chondrocytes. In cartilage of aging mice it was detected that the ALK1/ALK5 ratio is significantly increased, favoring TGF-beta signaling via the Smad1/5/8 route, inducing changes in chondrocyte differentiation and matrix metalloproteinase-13 (MMP-13) expression. Moreover, human OA cartilage showed a significant correlation between ALK1 and MMP-13 expression. Since in mice aging and OA in often goes hand in hand, we also analyzed age-related expression of TGF-beta superfamily related signaling molecules in healthy bovine cartilage in an age range from 6 months to 14 years. In this cohort of aging cartilage, we found that mainly signaling receptors determining the Smad2/3 pathway were decreased with age while Smad1/5/8-related signaling molecules did not alter, confirming our findings in aging mice.CONCLUSIONS: Old cartilage appears to be less protected by TGF-beta and shows significant alterations in TGF-beta signaling pathways. Loss of the protective Smad2/3 pathway during aging can provide an explanation for the relationship between OA and aging.