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

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

  • Cell Death Dis. 2021 May 25;12(6):533. doi: 10.1038/s41419-021-03800-x.
Yuheng Lu  # 1 2 3 4,  Liangliang Liu  # 1 2 3 4,  Jianying Pan  # 1 2 3 4,  Bingsheng Luo 1 2 3 4,  Hua Zeng 1 2 3 4,  Yan Shao 1 2 3 4,  Hongbo Zhang 1 2 3 4,  Hong Guan 1 2 3 4,  Dong Guo 1 2 3 4,  Chun Zeng 1 2 3 4,  Rongkai Zhang 1 2 3 4,  Xiaochun Bai 1 2 3 4,  Haiyan Zhang 5 6 7 8,  Daozhang Cai 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 2 Department of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 3 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
  • 4 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China.
  • 5 Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. zhhy0704@126.com.
  • 6 Department of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. zhhy0704@126.com.
  • 7 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China. zhhy0704@126.com.
  • 8 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China. zhhy0704@126.com.
  • 9 Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. cdz@smu.edu.cn.
  • 10 Department of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. cdz@smu.edu.cn.
  • 11 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China. cdz@smu.edu.cn.
  • 12 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China. cdz@smu.edu.cn.
  • # Contributed equally.
PMID: 34031369 DOI: 10.1038/s41419-021-03800-x
Abstract

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.

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