Targeting RORα in macrophages to boost diabetic bone regeneration

Abstract

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.

The specificities, influencing factors, and medical implications of bone circadian rhythms

“…On the contrary, the global knockout of Cry2 and mutation or knockout of Per2 in mice induces the proliferation of osteoblasts and represses the proliferation of osteoclasts, subsequently promoting bone mass and bone formation rate 21,29,30 . Besides anti‐inflammatory effects, Ror α induces the recruitment of BMSCs via a CCL3/IL‐6 depending manner and participates in osteoblast differentiation and metabolism by stimulating the expression of osteogenic markers 31,32 . Rev‐erb , as a transcriptional repressor, inhibits the expression of RANKL and reduces osteoclastogenesis by upregulating fatty acid‐binding protein 4 (FABP4) both in vivo and in vitro 33,34 .…”