Samumed, LLC, San Diego, CA, USA.
Formerly Samumed, LLC, USA.
Osteoarthritis Cartilage. 2019 Sep;27(9):1347-1360. doi: 10.1016/j.joca.2019.05.006. Epub 2019 May 25.
OBJECTIVES: Wnt pathway upregulation contributes to knee osteoarthritis (OA) through osteoblast differentiation, increased catabolic enzymes, and inflammation. The small-molecule Wnt pathway inhibitor, lorecivivint (SM04690), which previously demonstrated chondrogenesis and cartilage protection in an animal OA model, was evaluated to elucidate its mechanism of action. DESIGN: Biochemical assays measured kinase activity. Western blots measured protein phosphorylation in human mesenchymal stem cells (hMSCs), chondrocytes, and synovial fibroblasts. siRNA knockdown effects in hMSCs and BEAS-2B cells on Wnt pathway, chondrogenic genes, and LPS-induced inflammatory cytokines was measured by qPCR. In vivo anti-inflammation, pain, and function were evaluated following single intra-articular (IA) lorecivivint or vehicle injection in the monosodium iodoacetate (MIA)-induced rat OA model. RESULTS: Lorecivivint inhibited intranuclear kinases CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Lorecivivint inhibited CLK2-mediated phosphorylation of serine/arginine-rich (SR) splicing factors and DYRK1A-mediated phosphorylation of SIRT1 and FOXO1. siRNA knockdowns identified a role for CLK2 and DYRK1A in Wnt pathway modulation without affecting β-catenin with CLK2 inhibition inducing early chondrogenesis and DYRK1A inhibition enhancing mature chondrocyte function. NF-κB and STAT3 inhibition by lorecivivint reduced inflammation. DYRK1A knockdown was sufficient for anti-inflammatory effects, while combined DYRK1A/CLK2 knockdown enhanced this effect. In the MIA model, lorecivivint inhibited production of inflammatory cytokines and cartilage degradative enzymes, resulting in increased joint cartilage, decreased pain, and improved weight-bearing function. CONCLUSIONS: Lorecivivint inhibition of CLK2 and DYRK1A suggested a novel mechanism for Wnt pathway inhibition, enhancing chondrogenesis, chondrocyte function, and anti-inflammation. Lorecivivint shows potential to modify structure and improve symptoms of knee OA.
目的：Wnt 通路的上调通过成骨细胞分化、增加的分解代谢酶和炎症导致膝骨关节炎（OA）。小分子 Wnt 通路抑制剂 lorecivivint（SM04690）先前在动物 OA 模型中显示出软骨生成和软骨保护作用，其作用机制已被评估。
设计：生化测定测定激酶活性。Western blot 测定人间充质干细胞（hMSC）、软骨细胞和滑膜成纤维细胞中的蛋白质磷酸化。hMSC 和 BEAS-2B 细胞中 Wnt 通路、软骨生成基因和 LPS 诱导的炎症细胞因子的 siRNA 敲低效应通过 qPCR 进行测量。在单关节内（IA） lorecivivint 或载体注射后，在碘乙酸盐（MIA）诱导的大鼠 OA 模型中评估体内抗炎、疼痛和功能。
结果：Lorecivivint 抑制核内激酶 CDC 样激酶 2（CLK2）和双特异性酪氨酸磷酸化调节激酶 1A（DYRK1A）。Lorecivivint 抑制 CLK2 介导的丝氨酸/精氨酸丰富（SR）剪接因子磷酸化和 DYRK1A 介导的 SIRT1 和 FOXO1 磷酸化。siRNA 敲低确定了 CLK2 和 DYRK1A 在 Wnt 通路调节中的作用，而不影响β-连环蛋白，CLK2 抑制诱导早期软骨生成，DYRK1A 抑制增强成熟软骨细胞功能。Lorecivivint 抑制 NF-κB 和 STAT3 减少炎症。DYRK1A 敲低足以产生抗炎作用，而 DYRK1A/CLK2 联合敲低增强了这种作用。在 MIA 模型中，lorecivivint 抑制炎症细胞因子和软骨降解酶的产生，导致关节软骨增加、疼痛减轻和负重功能改善。
结论：Lorecivivint 抑制 CLK2 和 DYRK1A 提示了 Wnt 通路抑制的新机制，增强了软骨生成、软骨细胞功能和抗炎作用。Lorecivivint 有可能改变结构并改善膝骨关节炎的症状。
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