ArticleFrontiers in pharmacology2026
Rivaroxaban suppresses factor Xa-Driven PAR-2-ERK inflammatory, catabolic, osteoclastogenic, and mitochondrial dysfunction signaling in osteoarthritis-relevant chondrocytes: a drug-repurposing strategy for joint inflammation.
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Osteoarthritis (OA) is increasingly recognised as an inflammation-driven whole-joint disease in which cartilage catabolism, osteochondral remodelling, and mitochondrial dysfunction drive structural progression. Factor Xa (FXa), beyond haemostasis, is a signalling protease that activates protease-activated receptor-2 (PAR-2) and downstream MAPK-dependent inflammation; whether it directly drives this programme in OA-relevant chondrocytes, and whether rivaroxaban can intercept it, is undefined. Objective: To determine whether rivaroxaban attenuates FXa-induced PAR-2/ERK inflammatory signalling and downstream cytokine, catabolic, osteoclastogenic, and mitochondrial stress responses in bone marrow-derived mesenchymal stem cell (BMSC)-derived chondrocytes. Methods: Human BMSC-derived chondrocytes, phenotypically validated by collagen type II immunostaining and Alcian blue and toluidine blue staining, were exposed to non-cytotoxic FXa and rivaroxaban concentrations (MTT), with rivaroxaban-mediated FXa inhibition confirmed by an S-2765 chromogenic amidolytic assay. FXa-stimulated chondrocytes ± rivaroxaban were then profiled for PAR-2, ERK1/2, p-ERK1/2, DUSP6, TNF-α, IL-1β, MCP-1, SOX4, ADAMTS5, RANK/RANKL, and mitochondrial function by immunoblotting, RT-qPCR, ELISA, flow cytometry, and Rhodamine 123/Janus Green B staining; PAR-2 dependency was interrogated by siRNA-mediated Results: FXa elicited a coordinated phenotype-PAR-2 upregulation, ERK1/2 activation, increased TNF-α, IL-1β, and MCP-1, induction of SOX4 and ADAMTS5, enhanced RANK/RANKL, and mitochondrial dysfunction. Without compromising viability, rivaroxaban suppressed FXa amidolytic activity and reduced PAR-2 (transcript, total and cell-surface protein), ERK1/2 phosphorylation, p-ERK/ERK output, and DUSP6, denoting attenuated sustained ERK flux; this translated into lower cytokine secretion, diminished catabolic and osteoclastogenic effector expression, and preserved mitochondrial membrane potential and redox-associated staining. PAR-2 knockdown reduced, but did not abolish, the FXa response, indicating PAR-2-dominant but not exclusively PAR-2-dependent signalling. Conclusion: Rivaroxaban suppresses a coherent FXa-responsive inflammatory network in OA-relevant chondrocytes via the PAR-2-ERK axis and its downstream cytokine, catabolic, osteoclastogenic, and mitochondrial sequelae. These findings extend direct FXa inhibition beyond anticoagulation and support rivaroxaban as a mechanistically plausible repurposing candidate for OA-associated inflammatory pathology, pending validation in primary OA chondrocytes, osteochondral explants, and
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