MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway

作者：Lu, Yuheng; Liu, Liangliang; Pan, Jianying; Luo, Bingsheng; Zeng, Hua; Shao, Yan; Zhang, Hongbo; Guan, Hong; Guo, Dong; Zeng, Chun; Zhang, Rongkai; Bai, Xiaochun; Zhang, Haiyan; Cai, Daozhang

来源：Cell Death & Disease, 2021, 12(6): 533.

DOI：10.1038/s41419-021-03800-x

• ARTICULAR-CARTILAGE
• LUNG INJURY
• STEM-CELLS
• PROMOTES
• INFLAMMATION
• MICE

Milk fat globule-epidermal growth factor (EGF) factor 8 (MFG-E8), as a necessary bridging molecule between apoptotic cells and phagocytic cells, has been widely studied in various organs and diseases, while the effect of MFG-E8 in osteoarthritis (OA) remains unclear. Here, we identified MFG-E8 as a key factor mediating chondrocyte senescence and macrophage polarization and revealed its role in the pathology of OA. We found that MFG-E8 expression was downregulated both locally and systemically as OA advanced in patients with OA and in mice after destabilization of the medial meniscus surgery (DMM) to induce OA. MFG-E8 loss caused striking progressive articular cartilage damage, synovial hyperplasia, and massive osteophyte formation in OA mice, which was relieved by intra-articular administration of recombinant mouse MFG-E8 (rmMFG-E8). Moreover, MFG-E8 restored chondrocyte homeostasis, deferred chondrocyte senescence and reprogrammed macrophages to the M2 subtype to alleviate OA. Further studies showed that MFG-E8 was inhibited by miR-99b-5p, expression of which was significantly upregulated in OA cartilage, leading to exacerbation of experimental OA partially through activation of NF-kappa B signaling in chondrocytes. Our findings established an essential role of MFG-E8 in chondrocyte senescence and macrophage reprogramming during OA, and identified intra-articular injection of MFG-E8 as a potential therapeutic target for OA prevention and treatment.

• 单位
  南方医科大学