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.
Data availability statement
Data are available in a public, open access repository. Not applicable.
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Handling editor Josef S Smolen
HZ, YS and ZY contributed equally.
Contributors HyZ and XB conceived the ideas for experimental designs, analysed data and wrote the manuscript. HyZ and YS conducted the majority of the experiments and helped with manuscript preparation. ZY conducted the majority of the experiments and analysed data during the revision of the article. CZ, HbZ and LL performed immunohistochemistry and immunofluorescence and confocal imaging. HbZ and KL conducted cell cultures and western blot experiments. JY and ZY collected human tissue samples. CZ, XB and DC developed the concept, supervised the project and conceived the experiments. All authors approved the final version of the manuscript. XB accepted full responsibility for the finished work, had access to the data and controlled the decision to publish.
Funding This work was supported by grants from the National Natural Science Foundation of China (grant numbers 81974341, 81991510 and 81991511) and the Natural Science Foundation of Guangdong Province (2020A1515011062).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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