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

• Published in: Cell death & disease Vol. 12; no. 6; p. 533
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.05.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/95; 42/34; 45/77; 64/60; 692/420; 692/53/2423; 692/699/1670/407; 82; 82/1; 82/51; 82/80; 96/109; Antibodies; Apoptosis; Arthritis; Biochemistry; Biomedical and Life Sciences; Cartilage; Cartilage (articular); Cartilage diseases; Cell Biology; Cell Culture; Chondrocytes; Epidermal growth factor; Homeostasis; Hyperplasia; Immunology; Life Sciences; Macrophages; Meniscus; Milk fat globule membranes; NF-κB protein; Osteoarthritis; Phagocytes; Senescence; Surgery
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03800-x

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-κB 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.