1. Academic Validation
  2. Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7

Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7

  • Ann Rheum Dis. 2022 May;81(5):676-686. doi: 10.1136/annrheumdis-2021-221513.
Haiyan Zhang  # 1 2 Yan Shao  # 1 2 Zihao Yao  # 1 2 Liangliang Liu 1 2 Hongbo Zhang 1 2 Jianbin Yin 1 2 Haoyu Xie 1 2 Kai Li 1 2 Pinglin Lai 1 2 Hua Zeng 1 2 Guozhi Xiao 3 Chun Zeng 4 2 Daozhang Cai 4 2 Xiaochun Bai 4 2
Affiliations

Affiliations

  • 1 Department of Orthopedics, Academy of Orthopedics·Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Department of Joint Surgery, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third School of Clinical Medicine, Southern Medical University, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China.
  • 3 Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, China.
  • 4 Department of Orthopedics, Academy of Orthopedics·Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China baixc15@smu.edu.cn cdz@smu.edu.cn zengdavid@126.com.
  • # Contributed equally.
Abstract

Objectives: To investigate the role of mechanical stress in cartilage ageing and identify the mechanistic association during osteoarthritis (OA) progression.

Methods: F-box and WD repeat domain containing 7 (FBXW7) ubiquitin Ligase expression and chondrocyte senescence were examined in vitro, in experimental OA mice and in human OA cartilage. Mice with Fbxw7 knockout in chondrocytes were generated and adenovirus-expressing Fbxw7 (AAV-Fbxw7) was injected intra-articularly in mice. Destabilised medial meniscus surgery was performed to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score and the changes in chondrocyte senescence were determined. mRNA Sequencing was performed in articular cartilage from Fbxw7 knockout and control mice.

Results: Mechanical overloading accelerated senescence in cultured chondrocytes and in mice articular cartilage. FBXW7 was downregulated by mechanical overloading in primary chondrocytes and mice cartilage, and decreased in the cartilage of patients with OA, aged mice and OA mice. FBXW7 deletion in chondrocytes induced chondrocyte senescence and accelerated cartilage catabolism in mice, as manifested by an upregulation of p16INK4A, p21 and Colx and downregulation of Col2a1 and ACAN, which resulted in the exacerbation of OA. By contrast, intra-articular injection of adenovirus expressing Fbxw7 alleviated OA in mice. Mechanistically, mechanical overloading decreased Fbxw7 mRNA transcription and FBXW7-mediated MKK7 degradation, which consequently stimulated JNK signalling. In particular, inhibition of JNK activity by DTP3, a MKK7 inhibitor, ameliorated chondrocyte senescence and cartilage degeneration CONCLUSIONS: FBXW7 is a key factor in the association between mechanical overloading and chondrocyte senescence and cartilage ageing in the pathology of OA.

Keywords

chondrocytes; osteoarthritis; therapeutics.

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