Osteoarthritis
TRANSLATIONAL SCIENCE Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7 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, 1,2 Daozhang Cai , 1,2 Xiaochun Bai 1,2
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 p16 INK4A , 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. INTRODUCTION Osteoarthritis (OA) is the most common global age-related and post-traumatic degenerative joint disorder, which will become the disease with the highest disability rate globally by 2030. 1 2 Although mechanical overloading and advancing age have been recognised as the two most important risk factors for developing OA, much of the aetiology remains unkown. 3–5
Handling editor Josef S Smolen
Key messages
► Additional supplemental material is published online only. To view, please visit the journal online (http://dx.doi. org/1 0.1136/a nnrheumdis- 2021-2 21513). For numbered affiliations see end of article. Correspondence to Dr Xiaochun Bai, Professor Daozhang Cai and Dr Chun Zeng, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; b aixc15@smu.e du.cn, c dz@smu.e du.cn, z engdavid@126.c om
What is already known about this subject? ► Mechanical overloading and chondrocyte senescence play essential roles in osteoarthritis (OA) development. ► Fbxw7 deletion leads to p16 INK4a and p19 elevation to facilitate the cell cycle and promote cell senescence. What does this study add? ► F-box and WD repeat domain containing 7 (FBXW7), a ubiquitin ligase, is a key factor in the association between mechanical stress and chondrocyte senescence in OA pathology. ► Excessive mechanical loading downregulates FBXW7 to activate MKK7–JNK signalling, which stimulates chondrocyte senescence and consequently initiates and accelerates OA development.
HZ, YS and ZY contributed equally.
► Inhibition of JNK activity ameliorated chondrocyte senescence and cartilage degeneration.
Received 14 September 2021 Accepted 27 December 2021 Published Online First 20 January 2022
How might this impact on clinical practice or future developments? ► This study suggests that targeting FBXW7-
MKK7–JNK signalling may be a novel therapeutic approach for OA treatment.
Proper mechanical loading is essential for joint health, while mechanical overloading can result in articular cartilage being prone to degenerative lesions that lead to OA onset and progression. Due to the progressive loss of articular carti- lage that mainly occurs in load-bearing joints, OA was previously, for many decades, consid- ered to be a mechanical issue. 6 In the clinic, the knee axis of most patients with OA is misaligned, resulting in various deformities leading to further exacerbation of wear and accelerating OA prog- ress. 7 8 Previous studies have shown that a variety of signalling pathways are activated during OA progression. However, the specific mechanism through which mechanical overloading induces OA has not been fully elucidated. 9–11 Advancing age has been identified as the prom- inent biological mechanism for OA development
© Author(s) (or their employer(s)) 2022. No
To cite: Zhang H, Shao Y, Yao Z, et al . Ann Rheum Dis 2022; 81 :676–686. commercial re-use. See rights and permissions. Published by BMJ.
Zhang H, et al . Ann Rheum Dis 2022; 81 :676–686. doi:10.1136/annrheumdis-2021-221513
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