Synovial macrophage rhoa protects against osteoarthritis by suppressing YAP/IL-17C mediated chondrocyte senescence.

OBJECTIVE

The GTPase RhoA is known as a regulator involved in cartilage degeneration and subchondral bone remodeling related to osteoarthritis (OA). However, its specific role in synovial macrophages, the key immune cells of OA related tissues, remains entirely unexplored.

METHODS

Herein, the RhoA expression in human and mouse OA synovium was analyzed. A macrophage-specific RhoA conditional knockout (cKO) mouse model was generated. Histological staining, OARSI scoring, and micro-CT were used to assess cartilage damage, while Western blot, immunofluorescence staining, and ELISA assessed changes in cellular function. Transcriptome sequencing and validation of signaling pathways were conducted using tissues and cells from patients with OA and OA mice.

RESULTS

The collected results indicate that RhoA expression was significantly upregulated in synovial macrophages from OA patients and mice, correlating with disease severity. Contrary to its reported role in chondrocytes or endothelial cells, macrophage-specific RhoA deletion exacerbated OA, demonstrating enhanced cartilage destruction, subchondral bone loss, and synovitis. RhoA-deficient macrophages exhibited a pro-inflammatory M1 polarization and secreted high levels of IL-17C. This cytokine was necessary and sufficient to induce chondrocyte senescence, as evidenced by increased p53/p21, ROS, mitochondrial dysfunction, and suppressed autophagy, via activation of the PI3K/AKT/mTOR pathway. Mechanistically, RhoA ablation in macrophages activated the Hippo pathway effectors YAP/CCN2, leading to IL-17C transcription, independently of the canonical ROCK pathway.

CONCLUSION

In conclusion, present study reveals a previously unrecognized, protective role for macrophage RhoA in OA. It functions as a critical brake on a novel YAP-IL-17C axis, thereby preserving chondrocyte. This study redefines RhoA's role in joint homeostasis and nominates IL-17C as a potential therapeutic target for OA.