Wnt7a Inhibits IL-1β Induced Catabolic Gene Expression and Prevents Articular Cartilage Damage in Experimental Osteoarthritis.
Wnt7a Inhibits IL-1β Induced Catabolic Gene Expression and Prevents Articular Cartilage Damage in Experimental Osteoarthritis.
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DOI：
10.1038/srep41823
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发表时间：
2017-02-06
影响因子：
4.6
通讯作者：
Zeng L
中科院分区：
文献类型：
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作者：
Gibson AL;Hui Mingalone CK;Foote AT;Uchimura T;Zhang M;Zeng L
Wnt7a是一种在骨骼发育中起关键作用的蛋白质。然而，其在病理条件下对软骨稳态的影响尚不清楚。在本研究中，我们发现Wnt7a基因表达与个体OA软骨标本中MMP和IL-1β的表达呈独特的负相关。在原代人关节软骨细胞中异位表达后，Wnt7a抑制il -1β诱导的MMP和iNOS基因表达。Western blot分析表明，Wnt7a既诱导典型Wnt信号通路，也诱导NFAT和Akt非典型信号通路。有趣的是，抑制canonical和Akt通路并不影响Wnt7a的活性。然而，抑制NFAT通路会损害Wnt7a抑制MMP表达的能力，这表明Wnt7a需要NFAT信号才能发挥这一功能。在体内，关节内注射慢病毒Wnt7a可显著减轻内侧半月板失稳（DMM） oa诱导手术引起的小鼠关节软骨损伤。与此一致的是，Wnt7a也抑制了DMM动物关节MMP活性的进行性增加。这些结果表明，Wnt7a信号抑制炎症刺激诱导的人关节软骨细胞分解代谢基因表达，足以减弱小鼠实验性OA中MMP活性并促进关节软骨完整性，表明Wnt7a在调节OA发病机制中的新作用。
Wnt7a is a protein that plays a critical role in skeletal development. However, its effect on cartilage homeostasis under pathological conditions is not known. In this study, we found a unique inverse correlation between Wnt7a gene expression and that of MMP and IL-1β in individual human OA cartilage specimens. Upon ectopic expression in primary human articular chondrocytes, Wnt7a inhibited IL-1β-induced MMP and iNOS gene expression. Western blot analysis indicated that Wnt7a induced both canonical Wnt signaling and NFAT and Akt non-canonical signaling. Interestingly, inhibiting the canonical and Akt pathway did not affect Wnt7a activity. However, inhibiting the NFAT pathway impaired Wnt7a’s ability to inhibit MMP expression, suggesting that Wnt7a requires NFAT signaling to exert this function. In vivo, intraarticular injection of lentiviral Wnt7a strongly attenuated articular cartilage damage induced by destabilization of the medial meniscus (DMM) OA-inducing surgery in mice. Consistently, Wnt7a also inhibited the progressive increase of joint MMP activity in DMM animals. These results indicate that Wnt7a signaling inhibits inflammatory stimuli-induced catabolic gene expression in human articular chondrocytes and is sufficient to attenuate MMP activities and promote joint cartilage integrity in mouse experimental OA, demonstrating a novel effect of Wnt7a on regulating OA pathogenesis.