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Loss of mechanical stress induces synovitis, fibrosis and articular cartilage degeneration via distinct synovial cell subsets
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  • Published: 09 February 2026

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

  • Hisatoshi Ishikura1,
  • Hiroyuki Okada3,
  • Yota Kin1,
  • Ryota Chijimatsu2,
  • Junya Higuchi1,
  • Junya Miyahara1,
  • Naohiro Tachibana1,
  • Kosei Nagata1,
  • Asuka Terashima2,
  • Fumiko Yano2,
  • Yasunori Omata2,
  • Masahide Seki4,
  • Yutaka Suzuki4,
  • Roland Baron5,
  • Sakae Tanaka1 &
  • …
  • Taku Saito1 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cell biology
  • Diseases
  • Rheumatology

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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Data availability

The bulk and scRNA-seq data are available in the Gene Expression Omnibus under accession codes GSE200283 and GSE200898, respectively.

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Acknowledgements

We thank Junko Sugita, Keiko Kaneko, and Ryoko Honma for their technical assistance. We also extend our gratitude to Dr. Mitsutaka Yakabe (Geriatric Medicine, University of Tokyo) for teaching us the method for the mouse tail suspension model. We also thank Kazumi Abe and Yuuta Kuze (Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, University of Tokyo) for their technical advice on scRNA-seq.

Funding

This work was supported by JSPS KAKENHI grants 23H05484, 23K27718, 23K27717, 21K19552, 20H03799, 19H05654, 19H05565, and 18KK0254; the Nakatomi Foundation; and grants from the Japan Orthopaedics and Traumatology Research Foundation and the Hip Joint Foundation of Japan.

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Authors and Affiliations

  1. Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Hisatoshi Ishikura, Yota Kin, Junya Higuchi, Junya Miyahara, Naohiro Tachibana, Kosei Nagata, Sakae Tanaka & Taku Saito

  2. Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Ryota Chijimatsu, Asuka Terashima, Fumiko Yano & Yasunori Omata

  3. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113- 8655, Japan

    Hiroyuki Okada

  4. Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa City, Chiba, Japan

    Masahide Seki & Yutaka Suzuki

  5. Department of Medicine, Endocrine Unit, Harvard Medical School, MGH, Harvard School of Dental Medicine, 188 Longwood Ave, Boston, MA, USA

    Roland Baron

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Contributions

HI and TS designed the research project. HI, YK, JH, JM, NT, and KN performed histological experiments. HI, and RC performed RNA-seq and scRNA-seq on the advice of MS and YS. HI and HO conducted bioinformatics analysis. HI, AT, FY, YO, and TS performed figure editing. HI and TS wrote the manuscript with critical input from HO, YS, RB, and ST.

Corresponding author

Correspondence to Taku Saito.

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All mouse experiments were authorized to be approved by the Animal Care and Use Committee of the University of Tokyo (approval number M-P17-091). All methods were carried out in accordance with the relevant guidelines and regulations. All methods are reported in accordance with the ARRIVE guidelines (https://arriveguidelines.org).

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Ishikura, H., Okada, H., Kin, Y. et al. Loss of mechanical stress induces synovitis, fibrosis and articular cartilage degeneration via distinct synovial cell subsets. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39416-4

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  • Received: 01 December 2025

  • Accepted: 04 February 2026

  • Published: 09 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-39416-4

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