{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:15:37Z","timestamp":1788156937226,"version":"build-2803163510"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020917","name":"Mohammed Bin Rashid University of Medicine and Health Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020917","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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 \u00b1 rivaroxaban were then profiled for PAR-2, ERK1\/2, p-ERK1\/2, DUSP6, TNF-\u03b1, IL-1\u03b2, 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\n                      <jats:italic>F2RL1<\/jats:italic>\n                      knockdown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FXa elicited a coordinated phenotype\u2014PAR-2 upregulation, ERK1\/2 activation, increased TNF-\u03b1, IL-1\u03b2, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Rivaroxaban suppresses a coherent FXa-responsive inflammatory network in OA-relevant chondrocytes via the PAR-2\u2013ERK 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\n                      <jats:italic>in vivo<\/jats:italic>\n                      models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1872924","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:39:58Z","timestamp":1788154798000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rivaroxaban suppresses factor Xa\u2013Driven PAR-2\u2013ERK inflammatory, catabolic, osteoclastogenic, and mitochondrial dysfunction signaling in osteoarthritis-relevant chondrocytes: a drug-repurposing strategy for joint inflammation"],"prefix":"10.3389","volume":"17","author":[{"given":"Rajashree","family":"Patnaik","sequence":"first","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health","place":["Dubai, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirin","family":"Jannati","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health","place":["Dubai, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine F.","family":"Kellett","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health","place":["Dubai, United Arab Emirates"]},{"name":"Mediclinic City Hospital, Mediclinic Middle East","place":["Dubai, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline B.","family":"Hing","sequence":"additional","affiliation":[{"name":"Department of Trauma and Orthopaedic Surgery, St. George\u2019s Hospital","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajnavalka","family":"Banerjee","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health","place":["Dubai, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"367","DOI":"10.17305\/bjbms.2018.3323","article-title":"Simple, reliable, and time-efficient colorimetric method for the assessment of mitochondrial function and toxicity","volume":"18","author":"Ahmad","year":"2018","journal-title":"Bosn. 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