Abstract

Osteogenesis–angiogenesis coupling plays an important role during the occurrence of glucocorticoid-induced osteoporosis (GIOP), while the detailed pathophysiology is complex and yet to be elucidated. In this study, we investigated the role of Angiogenin (Ang), a pro-angiogenic ribonuclease secreted by mesenchymal stem cells, and its upstream regulation in GIOP. In vitro, we assessed the effects of Ang modulation on the viability, commitment, and pro-angiogenic capacity of dexamethasone (DEX)-treated bone marrow mesenchymal stem cells (BMSCs). In vivo, a mouse model of GIOP was constructed and Ang expression was modulated via tail-vein injection. Bone loss, trabecular structure, and type H vessels (CD31-high, endomucin-high; CD31 hi EMCN hi ) and their surrounding osteoblasts in the distal femur were evaluated using micro–computed tomography and histological staining. Furthermore, we explored the mechanistic role of ERK5 in regulating Ang expression. Results showed that Ang played an important role in regulating BMSC osteogenic commitment, viability and pro-angiogenic potential. DEX exposure compromised these effects by downregulating Ang and Ang overexpression effectively rescued DEX-induced BMSC dysfunction in vitro. Furthermore, Ang overexpression rescued DEX-induced bone loss and attenuated the impairment of osteogenesis–angiogenesis coupling in the distal femur by DEX. Mechanistically, ERK5 was capable of regulating the expression of Ang; ERK5 inhibition suppressed Ang expression, while ERK5 activation restored it. In conclusion, Glucocorticoids induce osteoporosis via inhibiting the ERK5/Ang signaling axis, thereby disrupting osteogenesis–angiogenesis coupling. Targeting this pathway via Ang overexpression offers a promising strategy to mitigate glucocorticoid-induced bone loss.