What question did this study set out to answer?

This research aims to clarify the mechanisms by which mechanical stress affects synovial and cartilage changes.

February 11, 2026Scientific Reports0 citationsOpen Access

Loss of mechanical stress induces synovitis, fibrosis and articular cartilage degeneration via distinct synovial cell subsets

HIHisatoshi IshikuraUniversity of Tokyo Hospital HOHiroyuki OkadaThe University of Tokyo YKYota KinJapan Sport Council

Key Points

This research aims to clarify the mechanisms by which mechanical stress affects synovial and cartilage changes.
Used a minimized mechanical stress (MMS) mouse model with knee joint immobilization and unloading.
Performed bulk RNA sequencing (RNA-seq) to analyze transcriptomic alterations.
Conducted single-cell RNA sequencing (scRNA-seq) to identify distinct synovial cell subsets.
Depleted macrophages using clodronate liposomes to assess their role in induced changes.
Synovitis was observed by day 3, followed by fibrosis and joint contracture within two weeks.
Gradual articular cartilage degeneration occurred after synovial alterations were noted.
Discontinuation of joint immobilization improved both synovial and cartilage changes.
RNA-seq identified ten cytokines correlated with cartilage changes.

Abstract

Joint function is impaired by disuse, as well as overuse. However, the underlying mechanisms remain unclear. Here, we elucidate the mechanisms of synovial and cartilage changes using a minimized mechanical stress (MMS) mouse model by combining knee joint immobilization and unloading. In this model, synovitis appeared by day 3, followed by subsequent fibrosis leading to joint contracture within two weeks. In contrast, articular cartilage degeneration developed gradually after the synovial alterations. Notably, synovial changes were attenuated by discontinuation of joint immobilization, while cartilage changes improved after discontinuation of joint immobilization and loading. Bulk RNA sequencing (RNA-seq) analyses supported the transcriptomic alterations for synovitis, fibrosis, and cartilage degeneration, and identified ten cytokines associated with cartilage changes. Single-cell RNA-seq (scRNA-seq) further identified distinct subsets in the MMS synovium: Lrrc15 + myofibroblasts and Mmp9 + macrophages, expressing many of these cytokines. Histological examination showed that MMS initially induced macrophage proliferation, while macrophage depletion by intra-articular administration of clodronate liposomes inhibited MMS-induced synovitis, fibrosis and cartilage degeneration, accompanied by a marked reduction in the MMS-distinct subsets. Our findings identified MMS-induced alterations in synovial cells and their roles in joint phenotype, suggesting that joint motion and mechanical loading contribute to the regulation of joint homeostasis.

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