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

## TL;DR

This study reveals that RhoA in synovial macrophages protects against osteoarthritis by preventing chondrocyte aging through a novel pathway involving YAP and IL-17C.

## Contribution

The study identifies a new protective role of macrophage RhoA in osteoarthritis by suppressing chondrocyte senescence via the YAP/IL-17C axis.

## Key findings

- Macrophage RhoA deficiency accelerates osteoarthritis progression.
- RhoA knockout in macrophages increases IL-17C secretion through the YAP/CCN2 pathway.
- IL-17C induces chondrocyte senescence via PI3K/AKT/mTOR signaling.

## Abstract

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.

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.

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.

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.

1. Macrophage RhoA deficiency accelerates OA progression2. RhoA knockout in macrophages enhances IL-17C secretion through YAP/CCN2 pathway3. IL-17C triggers chondrocyte senescence via PI3K/AKT/mTOR signaling

1. Macrophage RhoA deficiency accelerates OA progression

2. RhoA knockout in macrophages enhances IL-17C secretion through YAP/CCN2 pathway

3. IL-17C triggers chondrocyte senescence via PI3K/AKT/mTOR signaling

The online version contains supplementary material available at 10.1007/s10565-026-10151-w.