作者：Pérez-García S et

翻譯：劉佩玲

摘要：基於抑制金屬蛋白酶來治療骨關節炎（OA）方法的失敗，可能是因爲它們在體內平衡的組成型表達，以及它們的網絡複雜性。對這部分網絡的瞭解將有助於選擇目標病理靶點。從這個意義來說，阻斷鄰近關節細胞（如滑膜成纖維細胞：SF）產生的介質可以防止軟骨損傷。因此我們研究了ADAMTS-7/12對從SF到軟骨寡聚基質蛋白（COMP）降解的作用，以及參與它們表達的信號通路。我們首次報道了在SF中，ERK‐Runx2軸和Wnt/β‐連環素信號通路分別參與ADAMTS‐7/12的表達，其結果是軟骨細胞外基質的COMP降解。在用IL‐1β或纖連蛋白片段（Fn-fs）刺激後，我們發現ERK抑制降低了OA-SF中Runx2活化和ADAMTS-12表達，同樣減少了Fn-fs導致的COMP降解。通過DKK1阻斷Wnt信號通路亦可減少OA-SF中ADAMTS‐7表達和COMP降解。另外，Wnt7B的表達由IL‐1β和其自身誘導，還可增加ADAMTS‐7。我們的研究結果有助於開發針對ADAMTS‐7/12的疾病緩解OA藥物，用於預防細胞外基質成分的降解，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].