Targeting RORα in macrophages to boost diabetic bone regeneration

作者：Yufeng Shen, Qingming Tang, Jiajia Wang, Zheng Zhou, Ying Yin, Yifan Zhang, Wenhao Zheng, Xinyuan Wang, Guangjin Chen, Jiwei Sun, Lili Chen · 发表于：Cell Proliferation · 年份：2023 · DOI：10.1111/cpr.13474 · 被引用次数：19 · 研究领域：Bone Metabolism and Diseases、Bone and Dental Protein Studies、S100 Proteins and Annexins

Diabetes mellitus (DM) has become a serious threat to human health. Bone regeneration deficiency and nonunion caused by DM is perceived as a worldwide epidemic, with a very high socioeconomic impact on public health. Here, we find that targeted activation of retinoic acid-related orphan receptor α (RORα) by SR1078 in the early stage of bone defect repair can significantly promote in situ bone regeneration of DM rats. Bone regeneration relies on the activation of macrophage RORα in the early bone repair, but RORα of DM rats fails to upregulation as hyperglycemic inflammatory microenvironment induced IGF1-AMPK signalling deficiency. Mechanistic investigations suggest that RORα is vital for macrophage-induced migration and proliferation of bone mesenchymal stem cells (BMSCs) via a CCL3/IL-6 depending manner. In summary, our study identifies RORα expressed in macrophages during the early stage of bone defect repair is crucial for in situ bone regeneration, and offers a novel strategy for bone regeneration therapy and fracture repair in DM patients.