Tang Wen, Yin Jian-Bin, Lin Ren-Gui, Wu Chun-Yu, Huang Jia-Luo, Zhu Jin-Jian, Yang Ling-Feng, Li Guang-Ming, Cai Dao-Zhang, Liu Liang-Liang, Liu Yan-Li, Zhang Hai-Yan
Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Department of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics·Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
iScience. 2025 Mar 30;28(5):112131. doi: 10.1016/j.isci.2025.112131. eCollection 2025 May 16.
Evidence indicates that mechanical loading plays an important role in osteoarthritis (OA) progression, while the specific pathological changes of the synovium under excessive mechanical loading are unclear. Results showed that excessive mechanical loading caused pro-inflammation of synovial macrophages, which has been confirmed to exist in OA. High Rapgef3 expression level was found in RNA sequencing of RAW246.7 subjected to 0.5 Hz and 20% cyclic tensile strain. We verified this in the synovium of patients with OA and destabilization of the medial meniscus (DMM)-OA mice. Interestingly, the Rapgef3 content of chondrocytes was very low. Primary chondrocytes treated with Rapgef3 alone did not show metabolic phenotype, but an OA phenotype appeared when treated with Rapgef3-stimulated macrophage culture supernatant. Mechanically, excessive mechanical loading activated p65-nuclear factor κB (NF-κB) pathway through Rapgef3, which promoted the inflammation of macrophage, resulting in severe articular cartilage injury. Intra-articular Rapgef3 knockout reversed synovitis and cartilage degeneration, which might provide a therapeutic target for OA.
有证据表明机械负荷在骨关节炎（OA）进展中起重要作用，而滑膜在过度机械负荷下的具体病理变化尚不清楚。结果表明，过度机械负荷会导致滑膜巨噬细胞产生促炎反应，这在OA中已得到证实。在经受0.5Hz和20%循环拉伸应变的RAW246.7的RNA测序中发现Rapgef3表达水平较高。我们在OA患者和内侧半月板不稳定（DMM）-OA小鼠的滑膜中证实了这一点。有趣的是，软骨细胞中的Rapgef3含量非常低。单独用Rapgef3处理的原代软骨细胞未表现出代谢表型，但在用Rapgef3刺激的巨噬细胞培养上清液处理时出现了OA表型。从机制上讲，过度机械负荷通过Rapgef3激活p65-核因子κB（NF-κB）途径，促进巨噬细胞炎症，导致严重的关节软骨损伤。关节内Rapgef3基因敲除可逆转滑膜炎和软骨退变，这可能为OA提供一个治疗靶点。
