作者：Pérez-García S et

翻译：刘佩玲

摘要：基于抑制金属蛋白酶来治疗骨关节炎（OA）方法的失败，可能是因为它们在体内平衡的组成型表达，以及它们的网络复杂性。对这部分网络的了解将有助于选择目标病理靶点。从这个意义来说，阻断邻近关节细胞（如滑膜成纤维细胞：SF）产生的介质可以防止软骨损伤。因此我们研究了ADAMTS-7/12对从SF到软骨寡聚基质蛋白（COMP）降解的作用，以及参与它们表达的信号通路。我们首次报道了在SF中，ERK‐Runx2轴和Wnt/β‐连环素信号通路分别参与ADAMTS‐7/12的表达，其结果是软骨细胞外基质的COMP降解。在用IL‐1β或纤连蛋白片段（Fn-fs）刺激后，我们发现ERK抑制降低了OA-SF中Runx2活化和ADAMTS-12表达，同样减少了Fn-fs导致的COMP降解。通过DKK1阻断Wnt信号通路亦可减少OA-SF中ADAMTS‐7表达和COMP降解。另外，Wnt7B的表达由IL‐1β和其自身诱导，还可增加ADAMTS‐7。我们的研究结果有助于开发针对ADAMTS‐7/12的疾病缓解OA药物，用于预防细胞外基质成分的降解，如COMP。

附原文：Failure of therapeutic approaches for the treatment of osteoarthritis (OA) based on the inhibition of metalloproteinases, might be because of their constitutive expression in homeostasis, together with their network complexity. The knowledge of this network would contribute to selective target pathological conditions. In this sense, blockade of mediators produced by neighbouring joint cells, such as synovial fibroblasts (SF), would prevent cartilage damage. Thus, we studied the contribution of ADAMTS‐7 and ‐12 from SF to cartilage oligomeric matrix protein (COMP) degradation, and the signalling pathways involved in their expression. We report for the first time in SF, the involvement of ERK‐Runx2 axis and Wnt/β‐catenin signalling in ADAMTS‐12 and ADAMTS‐7 expressions, respectively, with the subsequent consequences in COMP degradation from cartilage extracellular matrix. After stimulation with IL‐1β or fibronectin fragments, we showed that ERK inhibition decreased Runx2 activation and ADAMTS‐12 expression in OA‐SF, also reducing Fn‐fs‐induced COMP degradation. Blockage of Wnt signalling by DKK1 reduced ADAMTS‐7 and COMP degradation in OA‐SF as well. In addition, Wnt7B expression was induced by IL‐1β and by itself, also increasing ADAMTS‐7. Our results could contribute to the development of disease‐modifying OA drugs targeting ADAMTS‐7 and‐12 for the prevention of extracellular matrix components degradation like COMP.

引自：Pérez-García S, Carrión M, Villanueva-Romero R et al. Wnt and RUNX2 mediate cartilage breakdown by osteoarthritis synovial fibroblast-derived ADAMTS-7 and -12. J Cell Mol Med. 2019 Mar 22. doi: 10.1111/jcmm.14283. [Epub ahead of print].