Downregulation of TGF-β1 in fibro-adipogenic progenitors initiates muscle ectopic mineralization

作者：La Li, Dai Li, Jingxian Zhu, Yiqun Wang, Feng Zhao, Jin Cheng, Rocky S. Tuan, Xiaoqing Hu, Yingfang Ao · 发表于：Journal of Bone and Mineral Research · 年份：2024 · DOI：10.1093/jbmr/zjae097 · 被引用次数：3 · 研究领域：Heterotopic Ossification and Related Conditions、Muscle Physiology and Disorders、TGF-β signaling in diseases

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 β1 (TGF-β1) expression in fibro-adipogenic progenitors (FAPs) was greatly downregulated. Since TGF-β1 is a strong immune suppressor and FAP's regulatory role has a large impact on muscle repair, we hypothesized that downregulation of TGF-β1 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 PDGFRα-positive FAPs...