A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee
A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee
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DOI：
10.1016/j.joca.2017.08.015
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发表时间：
2018-01-01
影响因子：
7
通讯作者：
Yazici, Y.
中科院分区：
文献类型：
--
作者：
Deshmukh, V.;Hu, H.;Yazici, Y.
目的：骨关节炎（OA）是一种以滑膜关节软骨丢失和软骨下骨增加为特征的退行性疾病。Wnt信号通路调节成骨细胞和软骨细胞的分化以及分解代谢蛋白酶的产生，从而影响骨性关节炎的发病机制。一种新型的小分子Wnt通路抑制剂SM04690在一系列体外和体内动物研究中进行了评估，以确定其对软骨形成、软骨保护和滑膜内衬关节病理的影响。设计：使用基于细胞的Wnt通路活性报告试验进行高通量筛选，以开发命名为SM04690的小分子。在骨髓来源的人间充质干细胞（hMSCs）中评估其特性，以评估软骨细胞分化以及通过免疫细胞化学和基因表达以及糖胺聚糖分解对软骨分解代谢的影响。在啮齿动物急性交叉韧带撕裂和部分内侧半月板切除术（ACLT thorn pMMx） OA模型中，采用生化和组织病理学技术测量SM04690对Wnt信号、软骨再生和保护的体内影响。结果：SM04690诱导hMSC分化为成熟的功能性软骨细胞，并降低软骨分解代谢标志物水平。单次关节内注射SM04690 （IA）在啮齿动物OA模型中有效，软骨厚度增加，软骨再生的证据，观察到软骨分解代谢的保护，导致国际骨关节炎研究学会（OARSI）组织学评分和生物标志物显著提高。结论：SM04690在OA大鼠模型中诱导软骨形成并抑制关节破坏，是OA潜在疾病修饰治疗的候选药物。(c) 2017作者。由Elsevier Ltd代表国际骨关节炎研究学会出版。
Objectives: Osteoarthritis (OA) is a degenerative disease characterized by loss of cartilage and increased subchondral bone within synovial joints. Wnt signaling affects the pathogenesis of OA as this pathway modulates both the differentiation of osteoblasts and chondrocytes, and production of catabolic proteases. A novel small-molecule Wnt pathway inhibitor, SM04690, was evaluated in a series of in vitro and in vivo animal studies to determine its effects on chondrogenesis, cartilage protection and synovial-lined joint pathology.Design: A high-throughput screen was performed using a cell-based reporter assay for Wnt pathway activity to develop a small molecule designated SM04690. Its properties were evaluated in bone-marrow-derived human mesenchymal stem cells (hMSCs) to assess chondrocyte differentiation and effects on cartilage catabolism by immunocytochemistry and gene expression, and glycosaminoglycan breakdown. In vivo effects of SM04690 on Wnt signaling, cartilage regeneration and protection were measured using biochemical and histopathological techniques in a rodent acute cruciate ligament tear and partial medial meniscectomy (ACLT thorn pMMx) OA model.Results: SM04690 induced hMSC differentiation into mature, functional chondrocytes and decreased cartilage catabolic marker levels compared to vehicle. A single SM04690 intra-articular (IA) injection was efficacious in a rodent OA model, with increased cartilage thickness, evidence for cartilage regeneration, and protection from cartilage catabolism observed, resulting in significantly improved Osteoarthritis Research Society International (OARSI) histology scores and biomarkers, compared to vehicle.Conclusions: SM04690 induced chondrogenesis and appeared to inhibit joint destruction in a rat OA model, and is a candidate for a potential disease modifying therapy for OA. (c) 2017 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.