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 of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Cell Death Dis. 2021 May 25;12(6):533. 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.
牛奶脂肪球-表皮生长因子 8（MFG-E8）作为凋亡细胞和吞噬细胞之间的必需桥接分子，已在各种器官和疾病中得到广泛研究，而 MFG-E8 在骨关节炎（OA）中的作用尚不清楚。在这里，我们确定 MFG-E8 是介导软骨细胞衰老和巨噬细胞极化的关键因素，并揭示了其在 OA 病理学中的作用。我们发现，MFG-E8 的表达在 OA 患者和内侧半月板手术（DMM）诱导 OA 的小鼠中均呈局部和系统性下调。MFG-E8 的缺失导致 OA 小鼠关节软骨进行性严重损伤、滑膜增生和大量骨赘形成，而关节内给予重组鼠 MFG-E8（rmMFG-E8）可缓解这种情况。此外，MFG-E8 恢复了软骨细胞的稳态，延缓了软骨细胞衰老，并将巨噬细胞重新编程为 M2 亚型，从而缓解 OA。进一步的研究表明，MFG-E8 受到 miR-99b-5p 的抑制，其在 OA 软骨中的表达显著上调，导致实验性 OA 部分通过 NF-κB 信号通路在软骨细胞中的激活而加重。我们的研究结果确立了 MFG-E8 在 OA 期间软骨细胞衰老和巨噬细胞重编程中的重要作用，并确定了关节内注射 MFG-E8 是预防和治疗 OA 的潜在治疗靶点。
