Long-term mechanical loading aggravates osteoarthritis through a pro-apoptotic inflammatory microenvironment

Abstract

Articular cartilage maintains joint homeostasis by adapting to mechanical loading, but both insufficient and excessive loading can impair cartilage integrity. Whether mechanical activity should be restricted in early osteoarthritis (OA), particularly among exercise enthusiasts, remains controversial. Here, we established in vitro and in vivo models of prolonged moderate mechanical loading (7.5% strain, 1 Hz) and analyzed human cartilage from weight-bearing and non-weight-bearing regions using RNA sequencing. Prolonged exposure (≥ 12 h) significantly increased chondrocyte apoptosis (2.3-fold), reduced expression of the chondrogenic transcription factor SOX9 and the matrix markers COL2A1, and elevated nerve growth factor (NGF) expression (1.8-fold), accompanied by enrichment of neural sensitization and inflammatory pathways. Immunofluorescence staining revealed NGF accumulation in mechanically stressed cartilage. Unlike high-intensity stress, which led to immediate apoptosis, moderate loading induced a delayed pro-apoptotic response after 12 h. These findings indicate that prolonged moderate mechanical loading may promote chondrocyte apoptosis through an NGF-mediated inflammatory microenvironment and provide mechanistic evidence suggesting that patients with early OA may benefit from limiting high-impact or prolonged moderate-intensity exercise sessions to prevent cartilage damage and guide rehabilitation.

Keywords

osteoarthritis / mechanical loading

Funding

This work was supported by the Zhejiang Medical and Health Innovation Talent Support Project (Grant No. 2021RC128 to S.S.), Zhejiang Medicine and Health Science and Technology Project (2025KY1540 to J.J.L.), Zhejiang Province Health Science and Technology Project (2024KY409 and 2021KY1086 to J.Y.L.), Huzhou Science and Technology Planning Project (2020GY10 to W.L., 2022GZ65 to J.Y.L.), Huzhou Basic and Clinical Translation of Orthopedics Key Laboratory (Grant No. HZGKSYS01Y to S.S.), and South Taihu Lake Outstanding Young Health Talents Cultivation Program (Grant No. rsk2023001 to S.S.).

Acknowledgements

The authors appreciate the crucial support the Central Laboratory of Huzhou Central Hospital provided throughout the entire process of this study. The authors gratefully acknowledge Figdraw (www.figdraw.com) for assistance with scientific illustration.

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