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

RhoA expression was significantly upregulated in synovial macrophages from OA patients and mice, correlating with disease severity.

• RhoA expression was analyzed in human and mouse OA synovium using Western blot, immunofluorescence staining, and ELISA.
• The upregulation of RhoA in synovial macrophages correlated with OA disease severity.
• This finding was observed in both human OA samples and mouse OA models.

Macrophage-specific RhoA conditional knockout (cKO) exacerbated OA, contrary to RhoA's reported role in chondrocytes or endothelial cells.

• A macrophage-specific RhoA conditional knockout (cKO) mouse model was generated to assess the role of macrophage RhoA in OA.
• Histological staining, OARSI scoring, and micro-CT were used to assess cartilage damage.
• RhoA-deficient mice showed enhanced cartilage destruction, subchondral bone loss, and synovitis compared to controls.
• This protective role of macrophage RhoA in OA was previously unrecognized and contrasts with its reported deleterious role in chondrocytes or endothelial cells.

RhoA-deficient macrophages exhibited pro-inflammatory M1 polarization and secreted high levels of IL-17C.

• Loss of RhoA in macrophages promoted a pro-inflammatory M1 polarization phenotype.
• RhoA-deficient macrophages secreted elevated levels of IL-17C.
• Changes in cellular function were assessed using Western blot, immunofluorescence staining, and ELISA.

IL-17C was necessary and sufficient to induce chondrocyte senescence.

• Chondrocyte senescence was evidenced by increased p53/p21, reactive oxygen species (ROS), mitochondrial dysfunction, and suppressed autophagy.
• IL-17C induced chondrocyte senescence via activation of the PI3K/AKT/mTOR pathway.
• The necessity and sufficiency of IL-17C in inducing chondrocyte senescence was validated using tissues and cells from OA patients and OA mice.

RhoA ablation in macrophages activated the Hippo pathway effectors YAP/CCN2, leading to IL-17C transcription independently of the canonical ROCK pathway.

• Mechanistic analysis identified YAP and CCN2 as downstream effectors activated upon RhoA deletion in macrophages.
• YAP/CCN2 activation led to IL-17C transcription in RhoA-deficient macrophages.
• This mechanism was independent of the canonical ROCK pathway.
• Transcriptome sequencing and signaling pathway validation were conducted using tissues and cells from OA patients and OA mice.

IL-17C is nominated as a potential therapeutic target for OA based on its role in mediating macrophage RhoA-deficiency-induced chondrocyte senescence.

• The study identified IL-17C as a key mediator in the YAP-IL-17C axis that drives chondrocyte senescence upon macrophage RhoA loss.
• IL-17C was described as both necessary and sufficient to induce detrimental changes in chondrocytes.
• The authors conclude that IL-17C represents 'a potential therapeutic target for OA.'