{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T21:04:42Z","timestamp":1765487082889,"version":"3.41.2"},"reference-count":38,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100004826","name":"Beijing Municipal Natural Science Foundation","doi-asserted-by":"publisher","award":["7232211"],"award-info":[{"award-number":["7232211"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023\u00a0M730123"],"award-info":[{"award-number":["2023\u00a0M730123"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972101","82172420","32000923"],"award-info":[{"award-number":["81972101","82172420","32000923"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In previous studies, we have demonstrated that stress response-induced high glucocorticoid levels could be the underlying cause of traumatic heterotopic ossification (HO), and we have developed a glucocorticoid-induced ectopic mineralization (EM) mouse model by systemic administration of a high dose of dexamethasone (DEX) to animals with muscle injury induced by cardiotoxin injection. In this model, dystrophic calcification (DC) developed into HO in a cell autonomous manner. However, it is not clear how DC is formed after DEX treatment. Therefore, in this study, we aimed to explore how glucocorticoids initiate muscle EM at a cellular and molecular level. We showed that DEX treatment inhibited inflammatory cell infiltration into injured muscle but inflammatory cytokine production in the muscle was significantly increased, suggesting that other non-inflammatory muscle cell types may regulate the inflammatory response and the muscle repair process. Accompanying this phenotype, transforming growth factor \u03b21 (TGF-\u03b21) expression in fibro-adipogenic progenitors (FAPs) was greatly downregulated. Since TGF-\u03b21 is a strong immune suppressor and FAP\u2019s regulatory role has a large impact on muscle repair, we hypothesized that downregulation of TGF-\u03b21 in FAPs after DEX treatment resulted in this hyperinflammatory state and subsequent failed muscle repair and EM formation. To test our hypothesis, we utilized a transgenic mouse model to specifically knockout Tgfb1 gene in PDGFR\u03b1-positive FAPs to investigate if the transgenic mice could recapitulate the phenotype that was induced by DEX treatment. Our results showed that the transgenic mice completely phenocopied this hyperinflammatory state and spontaneously developed EM following muscle injury. On the contrary, therapeutics that enhanced TGF-\u03b21 signaling in FAPs inhibited the inflammatory response and attenuated muscle EM. In summary, these results indicate that FAPs-derived TGF-\u03b21 is a key molecule in regulating muscle inflammatory response and subsequent EM, and that glucocorticoids exert their effect via downregulating TGF-\u03b21 in FAPs.<\/jats:p>","DOI":"10.1093\/jbmr\/zjae097","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T12:59:39Z","timestamp":1718801979000},"source":"Crossref","is-referenced-by-count":1,"title":["Downregulation of TGF-\u03b21 in fibro-adipogenic progenitors initiates muscle ectopic mineralization"],"prefix":"10.1093","author":[{"given":"La","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Sports Medicine of Peking University, Peking University Third Hospital Department of Sports Medicine, , Beijing 100191, China"},{"name":"Beijing Key Laboratory of Sports Injuries , Beijing 100191, China"},{"name":"Engineering Research Center of Sports Trauma Treatment Technology and Devices, Ministry of Education , Beijing 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