{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T14:13:28Z","timestamp":1794406408412,"version":"4.9.0"},"reference-count":40,"publisher":"Elsevier BV","issue":"5","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171133"],"award-info":[{"award-number":["32171133"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82322044"],"award-info":[{"award-number":["82322044"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010096","name":"Southern Medical University","doi-asserted-by":"publisher","award":["SMUL2021014"],"award-info":[{"award-number":["SMUL2021014"]}],"id":[{"id":"10.13039\/501100010096","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC3601900"],"award-info":[{"award-number":["2022YFC3601900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC3601902"],"award-info":[{"award-number":["2022YFC3601902"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["iScience"],"published-print":{"date-parts":[[2025,5]]},"DOI":"10.1016\/j.isci.2025.112131","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T18:23:52Z","timestamp":1743531832000},"page":"112131","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":5,"title":["Rapgef3 modulates macrophage reprogramming and exacerbates synovitis and osteoarthritis under excessive mechanical loading"],"prefix":"10.1016","volume":"28","author":[{"given":"Wen","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-bin","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren-gui","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-yu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-luo","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-jian","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-feng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang-ming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dao-zhang","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-liang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.isci.2025.112131_bib1","doi-asserted-by":"crossref","DOI":"10.1038\/nrdp.2016.72","article-title":"Osteoarthritis","volume":"2","author":"Martel-Pelletier","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"10.1016\/j.isci.2025.112131_bib2","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1136\/annrheumdis-2013-203355","article-title":"Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints","volume":"73","author":"Prieto-Alhambra","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"10.1016\/j.isci.2025.112131_bib3","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.joca.2019.12.004","article-title":"Osteoarthritis-related nociceptive behaviour following mechanical joint loading correlates with cartilage damage","volume":"28","author":"Ter Heegde","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"10.1016\/j.isci.2025.112131_bib4","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1002\/art.39707","article-title":"Association Between Overweight and Obesity and Risk of Clinically Diagnosed Knee, Hip, and Hand Osteoarthritis: A Population-Based Cohort Study","volume":"68","author":"Reyes","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"10.1016\/j.isci.2025.112131_bib5","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s00281-019-00762-3","article-title":"An emerging role for Toll-like receptors at the neuroimmune interface in osteoarthritis","volume":"41","author":"Miller","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"10.1016\/j.isci.2025.112131_bib6","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms15889","article-title":"DOT1L safeguards cartilage homeostasis and protects against osteoarthritis","volume":"8","author":"Monteagudo","year":"2017","journal-title":"Nat. Commun."},{"key":"10.1016\/j.isci.2025.112131_bib7","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jare.2022.01.004","article-title":"Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx","volume":"41","author":"Wang","year":"2022","journal-title":"J. Adv. Res."},{"key":"10.1016\/j.isci.2025.112131_bib8","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/s41467-019-09491-5","article-title":"Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-\u03baB pathway","volume":"10","author":"Chang","year":"2019","journal-title":"Nat. Commun."},{"key":"10.1016\/j.isci.2025.112131_bib9","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.actbio.2018.07.037","article-title":"Matrix degradation in osteoarthritis primes the superficial region of cartilage for mechanical damage","volume":"78","author":"Cooke","year":"2018","journal-title":"Acta Biomater."},{"key":"10.1016\/j.isci.2025.112131_bib10","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s41591-020-01192-7","article-title":"An algorithmic approach to reducing unexplained pain disparities in underserved populations","volume":"27","author":"Pierson","year":"2021","journal-title":"Nat. Med."},{"key":"10.1016\/j.isci.2025.112131_bib11","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1136\/annrheumdis-2021-221513","article-title":"Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7","volume":"81","author":"Zhang","year":"2022","journal-title":"Ann. Rheum. Dis."},{"key":"10.1016\/j.isci.2025.112131_bib12","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nrrheum.2016.136","article-title":"Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis","volume":"12","author":"Robinson","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"10.1016\/j.isci.2025.112131_bib13","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1177\/1759720X12467868","article-title":"Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations","volume":"5","author":"Sokolove","year":"2013","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"10.1016\/j.isci.2025.112131_bib14","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.joca.2020.01.007","article-title":"Macrophages regulate the progression of osteoarthritis","volume":"28","author":"Zhang","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"10.1016\/j.isci.2025.112131_bib15","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of proinflammatory cytokines in the pathophysiology of osteoarthritis","volume":"7","author":"Kapoor","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"10.1016\/j.isci.2025.112131_bib16","first-page":"5009","article-title":"Imbalance of M1\/M2 macrophages is linked to severity level of knee osteoarthritis","volume":"16","author":"Liu","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"10.1016\/j.isci.2025.112131_bib17","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202207490","article-title":"Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis","volume":"10","author":"Yan","year":"2023","journal-title":"Adv. Sci."},{"key":"10.1016\/j.isci.2025.112131_bib18","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1136\/annrheumdis-2018-213450","article-title":"Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2","volume":"77","author":"Zhang","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"10.1016\/j.isci.2025.112131_bib19","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1124\/pr.110.003707","article-title":"Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions","volume":"65","author":"Schmidt","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"10.1016\/j.isci.2025.112131_bib20","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1161\/ATVBAHA.115.306534","article-title":"Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation","volume":"35","author":"Kato","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"10.1016\/j.isci.2025.112131_bib21","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/1541-7786.MCR-22-0026","article-title":"EPAC Regulates Melanoma Growth by Stimulating mTORC1 Signaling and Loss of EPAC Signaling Dependence Correlates with Melanoma Progression","volume":"20","author":"Krishnan","year":"2022","journal-title":"Mol. Cancer Res."},{"key":"10.1016\/j.isci.2025.112131_bib22","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20190930","article-title":"Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension","volume":"217","author":"Liu","year":"2020","journal-title":"J. Exp. Med."},{"key":"10.1016\/j.isci.2025.112131_bib23","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1152\/physrev.00025.2017","article-title":"Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development","volume":"98","author":"Robichaux","year":"2018","journal-title":"Physiol. Rev."},{"key":"10.1016\/j.isci.2025.112131_bib24","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1093\/abbs\/gmx045","article-title":"Lithium and an EPAC-specific inhibitor ESI-09 synergistically suppress pancreatic cancer cell proliferation and survival","volume":"49","author":"Wang","year":"2017","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"10.1016\/j.isci.2025.112131_bib25","doi-asserted-by":"crossref","first-page":"4901","DOI":"10.1096\/fj.14-255703","article-title":"Activation of EPAC1\/2 is essential for osteoclast formation by modulating NF\u03baB nuclear translocation and actin cytoskeleton rearrangements","volume":"28","author":"Mediero","year":"2014","journal-title":"FASEB J."},{"key":"10.1016\/j.isci.2025.112131_bib26","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/bph.12103","article-title":"Prostaglandin E2-induced intercellular adhesion molecule-1 expression is mediated by cAMP\/Epac signalling modules in bEnd.3 brain endothelial cells","volume":"169","author":"Park","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.isci.2025.112131_bib27","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nri.2017.52","article-title":"The non-canonical NF-\u03baB pathway in immunity and inflammation","volume":"17","author":"Sun","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.isci.2025.112131_bib28","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/s41419-020-2314-6","article-title":"NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis","volume":"11","author":"Liu","year":"2020","journal-title":"Cell Death Dis."},{"key":"10.1016\/j.isci.2025.112131_bib29","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1038\/s41467-021-21514-8","article-title":"RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming","volume":"12","author":"Yin","year":"2021","journal-title":"Nat. Commun."},{"key":"10.1016\/j.isci.2025.112131_bib30","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2021.103283","article-title":"Decreased miR-214-3p activates NF-\u03baB pathway and aggravates osteoarthritis progression","volume":"65","author":"Cao","year":"2021","journal-title":"EBioMedicine"},{"key":"10.1016\/j.isci.2025.112131_bib31","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41584-023-00966-w","article-title":"Matrix metalloproteinases in arthritis: towards precision medicine","volume":"19","author":"Grillet","year":"2023","journal-title":"Nat. Rev. Rheumatol."},{"key":"10.1016\/j.isci.2025.112131_bib32","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s13075-022-02859-x","article-title":"Senescence in osteoarthritis: from mechanism to potential treatment","volume":"24","author":"Liu","year":"2022","journal-title":"Arthritis Res. Ther."},{"key":"10.1016\/j.isci.2025.112131_bib33","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jot.2020.09.006","article-title":"Chondrocyte ferroptosis contribute to the progression of osteoarthritis","volume":"27","author":"Yao","year":"2021","journal-title":"J. Orthop. Translat."},{"key":"10.1016\/j.isci.2025.112131_bib34","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.joca.2015.09.019","article-title":"Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration","volume":"24","author":"Wang","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"10.1016\/j.isci.2025.112131_bib35","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.cellsig.2013.11.004","article-title":"Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways","volume":"26","author":"Zhou","year":"2014","journal-title":"Cell. Signal."},{"key":"10.1016\/j.isci.2025.112131_bib36","doi-asserted-by":"crossref","DOI":"10.1155\/2017\/2860956","article-title":"Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1\u03b2 in Retinal Endothelial Cells and Mouse Retinal Vasculature","volume":"2017","author":"Jiang","year":"2017","journal-title":"Mediators Inflamm."},{"key":"10.1016\/j.isci.2025.112131_bib37","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/j.1365-2559.2006.02508.x","article-title":"Synovitis score: discrimination between chronic low-grade and high-grade synovitis","volume":"49","author":"Krenn","year":"2006","journal-title":"Histopathology"},{"key":"10.1016\/j.isci.2025.112131_bib38","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1016\/j.joca.2010.05.025","article-title":"The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse","volume":"18","author":"Glasson","year":"2010","journal-title":"Osteoarthr. Cartil."},{"key":"10.1016\/j.isci.2025.112131_bib39","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1002\/art.22254","article-title":"Effects of chronic growth hormone and insulin-like growth factor 1 deficiency on osteoarthritis severity in rat knee joints","volume":"54","author":"Ekenstedt","year":"2006","journal-title":"Arthritis Rheum."},{"key":"10.1016\/j.isci.2025.112131_bib40","doi-asserted-by":"crossref","first-page":"16805","DOI":"10.1074\/jbc.M112024200","article-title":"Stimulation of phospholipase C-epsilon by the M3 muscarinic acetylcholine receptor mediated by cyclic AMP and the GTPase Rap2B","volume":"277","author":"Evellin","year":"2002","journal-title":"J. Biol. Chem."}],"container-title":["iScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2589004225003918?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2589004225003918?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:49:39Z","timestamp":1776905379000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2589004225003918"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5]]},"references-count":40,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["S2589004225003918"],"URL":"https:\/\/doi.org\/10.1016\/j.isci.2025.112131","relation":{},"ISSN":["2589-0042"],"issn-type":[{"value":"2589-0042","type":"print"}],"subject":[],"published":{"date-parts":[[2025,5]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Rapgef3 modulates macrophage reprogramming and exacerbates synovitis and osteoarthritis under excessive mechanical loading","name":"articletitle","label":"Article Title"},{"value":"iScience","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.isci.2025.112131","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 The Author(s). Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"112131"}}