CD34hi subset of synovial fibroblasts contributes to fibrotic phenotype of human knee osteoarthritis
Osteoarthritis (OA) shows various clinical manifestations depending on the status of its joint components. We aimed to identify the synovial cell subsets responsible for OA pathophysiology by comprehensive analyses of human synovium samples in single-cell resolution. Two distinct OA synovial tissue groups were classified by gene expression profiles in RNA-Seq: inflammatory and fibrotic. The inflammatory group exhibited high expression of inflammatory cytokines, histologically inflammatory infiltrate, and a more severe pain score. The fibrotic group showed higher expression of fibroblast growth factor (FGFs) and bone morphogenetic proteins (BMPs), showed histologically perivascular fibrosis, and showed a lower pain score. In single-cell RNA-Seq (scRNA-Seq) of synovial cells, MERTKloCD206lo macrophages and CD34hi fibroblasts were associated with the inflammatory and fibrotic groups, respectively. Among the 3 fibroblast subsets, CD34loTHY1lo and CD34loTHY1hi fibroblasts were influenced by synovial immune cells, whereas CD34hi fibroblasts were influenced by mural and endothelial cells. Particularly, in CD34hi fibroblast subsets, CD34hiCD70hi fibroblasts promoted proliferation of Tregs, potentially suppressing synovitis and protecting articular cartilage. Elucidation of the mechanisms underlying the regulation of these synovial cell subsets may lead to novel strategies for OA therapeutics.
Authors
- Hiroshi Inui (ORCID: https://orcid.org/0000-0002-3605-2238)
- Yasuhide Iwanaga (ORCID: https://orcid.org/0000-0001-6419-3735)
- Yasunori Omata (ORCID: https://orcid.org/0000-0002-8912-7483)
- Taku Saito (ORCID: https://orcid.org/0000-0003-4911-3930)
- Ryota Chijimatsu
- Yutaka Suzuki (ORCID: https://orcid.org/0000-0002-7559-5139)
- Shoichiro Tani (ORCID: https://orcid.org/0000-0003-3090-5073)
- Ryota Yamagami (ORCID: https://orcid.org/0000-0002-9150-4911)
- Hisatoshi Ishikura (ORCID: https://orcid.org/0000-0001-6317-6087)
- Naohiro Tachibana (ORCID: https://orcid.org/0000-0002-1073-5823)
- Masahide Seki (ORCID: https://orcid.org/0000-0001-6091-8698)
- Junya Miyahara (ORCID: https://orcid.org/0000-0002-6369-5829)
- Roland Baron (ORCID: https://orcid.org/0000-0001-5784-5934)
- Sakae Tanaka (ORCID: https://orcid.org/0000-0001-9210-9414)
- Hiroyuki Okada (ORCID: https://orcid.org/0000-0003-4217-1548)
- Junya Higuchi
- Shuji Taketomi (ORCID: https://orcid.org/0000-0002-4994-2504)
- Asuka Terashima (ORCID: https://orcid.org/0000-0001-5150-5656)
- Kosei Nagata (ORCID: https://orcid.org/0000-0003-4495-1134)
- Kenichi Kono (ORCID: https://orcid.org/0000-0001-8033-2037)
- Kohei Kawaguchi (ORCID: https://orcid.org/0000-0001-8541-1092)
- Fumiko Yano (ORCID: https://orcid.org/0000-0002-0602-1094)
Institutions
- Harvard University (US)
- Sensor Electronics (United States) (US)
- Integrative Medicine Institute (US)
- Laboratoire d’immunologie intégrative du cancer (FR)
- The University of Tokyo (JP)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1172/jci.insight.183690
- Citations
- 14
- Primary Topic
- Osteoarthritis Treatment and Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 23.35
Funders
- Nakatomi Foundation
- Japan Society for the Promotion of Science