A novel disease-modifying osteoarthritis drug candidate targeting Runx1
A novel disease-modifying osteoarthritis drug candidate targeting Runx1
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DOI：
10.1136/annrheumdis-2012-201745
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发表时间：
2013-05-01
影响因子：
27.4
通讯作者：
Chung, Ung-il
中科院分区：
文献类型：
--
作者：
Yano, Fumiko;Hojo, Hironori;Chung, Ung-il
目的寻找一种新的疾病改善性骨关节炎药物（DMOAD）候选药物，通过促进软骨分化来有效修复软骨，并通过抑制异常肥大来阻止骨关节炎（OA）的进展。方法采用Col2GFP-ATDC5系统，通过四步筛选了2500种天然和合成的小分子软骨形成药物，并鉴定出一种小分子噻吩茚唑衍生物TD-198946作为新的DMOAD候选药物。我们在OA发病时（预防模型）和OA诱导后4周（修复模型），通过关节内注射直接进入关节间隙，测试了其作为DMOAD的功效。通过芯片分析筛选下游分子。我们进一步通过体外和体内实验研究了该药物的作用机制及其分子靶点。结果TD-198946在细胞和跖器官培养中具有强烈的软骨分化诱导作用，但不促进肥大。当直接应用于关节间隙时，TD-198946成功地预防和修复了关节软骨的退变。TD-198946通过调节Runx1的表达发挥作用，与正常组织相比，小鼠和人OA软骨中Runx1的表达均下调。我们的数据表明，TD-198946是一类新的DMOAD候选者，靶向Runx1将为开发针对OA的疾病改善药物提供一条有希望的新途径。
Objectives To identify a new disease-modifying osteoarthritis drug (DMOAD) candidate that can effectively repair cartilage by promoting chondrogenic differentiation and halt osteoarthritis (OA) progression by suppressing aberrant hypertrophy.Methods We screened 2500 natural and synthetic small compounds for chondrogenic agents via four steps using the Col2GFP-ATDC5 system and identified a small thienoindazole derivative compound, TD-198946, as a novel DMOAD candidate. We tested its efficacy as a DMOAD via intra-articular injections directly into the joint space in a surgically-induced mouse model of OA both at the onset (prevention model) and 4 weeks after (repair model) OA induction. The downstream molecules were screened by microarray analysis. We further investigated the mechanism of the drug action and its molecular target using in vitro and in vivo assays.Results TD-198946 strongly induced chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. When administered directly into the joint space, TD-198946 successfully prevented and repaired degeneration of the articular cartilage. TD-198946 exerted its effect through the regulation of Runx1 expression, which was downregulated in both mouse and human OA cartilage compared with normal tissue.Conclusions Our data suggest that TD-198946 is a novel class of DMOAD candidate, and that targeting Runx1 will provide a promising new approach in the development of disease-modifying drugs against OA.