Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Pharmacol Res. 2019 Jan;139:314-324. doi: 10.1016/j.phrs.2018.09.026. Epub 2018 Sep 28.
Osteoarthritis (OA) is a degenerative disease characterized by progressive loss of cartilage, osteophyte formation and subchondral bone sclerosis. Although some animal experiments have reported that fibroblast growth factor 18 (FGF18) attenuates cartilage degradation, the effect of FGF18 on chondrocytes and its underlying mechanism at the cellular level remain largely unknown. In this study, we found that an intra-articular injection of FGF18 attenuates cartilage degradation, increases Collagen II deposition and suppresses matrix metallopeptidase 13 (MMP13) expression in rat post-traumatic osteoarthritis (PTOA). At the cellular level, FGF18 promotes chondrocyte proliferation through PI3K-AKT signaling and migration through PI3K signaling. We found that FGF18 attenuates IL-1β-induced apoptosis, restores mitochondrial function and reduces Reactive Oxygen Species (ROS) production through PI3K-AKT signaling. Moreover, the mitochondrial fusion and fission of chondrocytes were enhanced by a short duration of treatment (within 24 h) of IL-1β and suppressed by prolonged treatment (48 h). FGF18 significantly enhances the mitochondrial fusion and fission, restoring mitochondrial function and morphology, and reduces ROS production. We also found that the FGFR1/FGFR3 ratio, which might contribute to the progression of osteoarthritis, was upregulated by IL-1β and downregulated by FGF18. To the best of our knowledge, our data demonstrated the anti-osteoarthritic effect of FGF18 at the cellular level for the first time and suggested that PI3K-AKT signaling and mitochondrial fusion and fission might play critical roles during the process. Our study proved that FGF18 might be a promising drug for the treatment of early stage osteoarthritis and is worth further study.
骨关节炎（OA）是一种退行性疾病，其特征是软骨进行性丧失、骨赘形成和软骨下骨硬化。虽然一些动物实验报道成纤维细胞生长因子 18（FGF18）可减轻软骨降解，但 FGF18 对软骨细胞的影响及其在细胞水平上的潜在机制在很大程度上仍不清楚。在这项研究中，我们发现关节内注射 FGF18 可减轻大鼠创伤后骨关节炎（PTOA）的软骨降解，增加 Collagen II 沉积并抑制基质金属蛋白酶 13（MMP13）的表达。在细胞水平上，FGF18 通过 PI3K-AKT 信号通路促进软骨细胞增殖，通过 PI3K 信号通路促进迁移。我们发现 FGF18 通过 PI3K-AKT 信号通路减轻 IL-1β诱导的细胞凋亡，恢复线粒体功能并减少活性氧物质（ROS）的产生。此外，通过短暂（24 小时内）IL-1β处理增强软骨细胞的线粒体融合和裂变，通过延长（48 小时）处理抑制线粒体融合和裂变。FGF18 显著增强线粒体融合和裂变，恢复线粒体功能和形态，减少 ROS 产生。我们还发现，可能导致骨关节炎进展的 FGFR1/FGFR3 比值被 IL-1β上调，被 FGF18 下调。据我们所知，我们的数据首次在细胞水平上证明了 FGF18 的抗骨关节炎作用，并表明 PI3K-AKT 信号通路和线粒体融合和裂变可能在这一过程中发挥关键作用。我们的研究证明 FGF18 可能是治疗早期骨关节炎的一种有前途的药物，值得进一步研究。
