Senescent Synovial Intimal Fibroblasts Aggravate Osteoarthritis by Regulating Macrophage Polarization and Chondrocyte Phenotype Through ANGPTL4‐α5β1 Axis

Jan 23, 2026Advanced science (Weinheim, Baden-Wurttemberg, Germany)

Aging joint lining cells may worsen osteoarthritis by changing immune cell type and cartilage cell behavior through the ANGPTL4-α5β1 pathway

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Abstract

Synovial intimal fibroblasts (SIF) exhibit more pronounced premature senescence compared to other synovial cell types.

The accumulation of senescent cells in the synovium is linked to the development of osteoarthritis.
A specific subpopulation of senescent SIF has been identified, influenced by the transcription factors EGR1 and ATF3.
Senescent SIF may promote the polarization of M1 macrophages, which is associated with cartilage degeneration.
Paracrine secretion of ANGPTL4 from senescent SIF could contribute to the progression of osteoarthritis.
Direct cell-cell contact between senescent SIF and macrophages may play a role in osteoarthritis development.

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The incidence of osteoarthritis (OA) is strongly correlated with aging. It has been shown that the accumulation of senescent cells in the synovium precedes chondrocyte senescence and cartilage degradation, suggesting that synovial cell senescence plays a key role in OA pathogenesis. This study aimed to investigate the mechanisms underlying synovial cell senescence and its influence on intercellular communication within the joint. Using multiplex immunofluorescence, gene regulatory network reconstruction, and single-cell RNA sequencing analyses, we identified senescent cells and characterized the senescence-associated secretory phenotype in the synovium. A series of in vivo and in vitro functional experiments is conducted to elucidate the mechanisms of fibroblast senescence and its effects on macrophages and chondrocytes. We found that synovial intimal fibroblasts (SIF) display more marked premature senescence compared to other synovial cell types. A specific senescent subpopulation within SIF is identified, and we demonstrated that the transcription factors EGR1 and ATF3 regulate senescence-related pathways in these cells. Furthermore, we showed that senescent SIF promote M1 macrophage polarization and cartilage degeneration through paracrine secretion of ANGPTL4. Additionally, senescent SIF may facilitate OA progression through direct cell-cell contact with macrophages.

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Senescent Synovial Intimal Fibroblasts Aggravate Osteoarthritis by Regulating Macrophage Polarization and Chondrocyte Phenotype Through ANGPTL4‐α5β1 Axis

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