Samumed, LLC, San Diego, CA, USA.
University of California, Davis, CA, USA.
Osteoarthritis Cartilage. 2018 Jan;26(1):18-27. doi: 10.1016/j.joca.2017.08.015. Epub 2017 Sep 6.
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.
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 + pMMx) OA model.
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.
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.
骨关节炎（OA）是一种退行性疾病，其特征是滑膜关节内软骨丧失和软骨下骨增加。Wnt 信号通路影响 OA 的发病机制，因为该途径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。一种新型小分子 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，以确定其对软骨生成、软骨保护和滑膜衬里关节病理的影响。
使用基于细胞的 Wnt 通路活性报告基因检测进行高通量筛选，开发出一种名为 SM04690 的小分子。在骨髓源性人间充质干细胞（hMSC）中评估其特性，以评估软骨细胞分化以及免疫细胞化学和基因表达和糖胺聚糖分解对软骨分解代谢的影响。在大鼠急性前交叉韧带撕裂和部分内侧半月板切除术（ACLT+pMMx）OA 模型中，使用生化和组织病理学技术测量 SM04690 对 Wnt 信号转导、软骨再生和保护的体内作用。
SM04690 诱导 hMSC 分化为成熟、功能齐全的软骨细胞，并降低软骨分解代谢标志物水平，与载体相比。单次关节内（IA）注射 SM04690 在大鼠 OA 模型中有效，增加了软骨厚度，观察到软骨再生的证据，并防止了软骨分解代谢，与载体相比，OARSI 组织学评分和生物标志物得到了显著改善。
SM04690 诱导软骨生成，并似乎抑制大鼠 OA 模型中的关节破坏，是 OA 潜在的疾病修饰治疗的候选药物。
