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

## TL;DR

Senescent synovial fibroblasts worsen osteoarthritis by influencing macrophages and cartilage through a specific signaling pathway.

## Contribution

Identifies senescent synovial intimal fibroblasts as key OA drivers via the ANGPTL4–α5β1 axis regulated by EGR1 and ATF3.

## Key findings

- Senescent synovial intimal fibroblasts promote M1 macrophage polarization.
- ANGPTL4–α5β1 signaling facilitates cartilage degeneration and OA progression.
- Pharmacological inhibition of this pathway reduces disease severity.

## Abstract

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.

Senescent synovial intimal fibroblasts (SIF) are identified as key drivers of osteoarthritis. They promote M1 macrophage polarization and cartilage degeneration via the ANGPTL4–α5β1 axis, regulated by transcription factors EGR1 and ATF3. Pharmacological inhibition of this pathway alleviates disease, revealing SIF senescence as a promising therapeutic target for OA.