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
  • 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. [email protected].
  • 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. [email protected].
  • 7. The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China. [email protected].
  • 8. Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China. [email protected].
  • 9. Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. [email protected].
  • 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. [email protected].
  • 11. The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China. [email protected].
  • 12. Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China. [email protected].
  • # 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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