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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,9]]},"abstract":"<jats:p>\n                    Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to systemic and articular bone loss by activating bone resorption and suppressing bone formation. Despite current therapeutic agents, inflammation-induced bone loss in RA continues to be a significant clinical problem due to joint deformity and lack of articular and systemic bone repair. Here, we identify the suppressor of bone formation, Schnurri-3 (SHN3), as a potential target to prevent bone loss in RA. SHN3 expression in osteoblast-lineage cells is induced by proinflammatory cytokines. Germline deletion or conditional deletion of\n                    <jats:italic>Shn3<\/jats:italic>\n                    in osteoblasts limits articular bone erosion and systemic bone loss in mouse models of RA. Similarly, silencing of SHN3 expression in these RA models using systemic delivery of a bone-targeting recombinant adenoassociated virus protects against inflammation-induced bone loss. In osteoblasts, TNF activates SHN3 via ERK MAPK-mediated phosphorylation and, in turn, phosphorylated SHN3 inhibits WNT\/\u03b2-catenin signaling and up-regulates RANKL expression. Accordingly, knock-in of a mutation in\n                    <jats:italic>Shn3<\/jats:italic>\n                    that fails to bind ERK MAPK promotes bone formation in mice overexpressing human TNF due to augmented WNT\/\u03b2-catenin signaling. Remarkably, Shn3-deficient osteoblasts are not only resistant to TNF-induced suppression of osteogenesis, but also down-regulate osteoclast development. Collectively, these findings demonstrate SHN3 inhibition as a promising approach to limit bone loss and promote bone repair in RA.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2218019120","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T13:14:43Z","timestamp":1683206083000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":28,"title":["Schnurri-3 inhibition suppresses bone and joint damage in models of rheumatoid arthritis"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1486-3336","authenticated-orcid":false,"given":"Zheni","family":"Stavre","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA 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