Exosomes from bone marrow mesenchymal stem cells inhibit osteoclast differentiation and alleviate osteoporosis via RBM15B/YAP1 to induce autophagy.

BACKGROUND

Osteoporosis develops primarily as a result of an imbalance between osteoclastic bone resorption and osteoblastic bone formation. Bone marrow mesenchymal stem cells-derived-exosomes (BMSCs-Exos) regulate osteoclast differentiation and osteoporosis in recent studies. But the mechanisms are still unclear. This research aimed to explore the mechanisms of BMSCs-Exos in osteoclast differentiation and osteoporosis.

METHODS

Exosomes were extracted from BMSCs. THP-1 cells were cultured and treated with BMSCs-Exos. Osteoclast- and autophagy-related gene expression was assessed by qPCR and Western blot, the regulation of YAP1 by RBM15B was analyzed by MeRIP and RNA pull-down, osteoclast differentiation was detected by TRAP staining. HE staining, immunohistochemical staining and micro-CT were employed to assess the impact of BMSCs-Exos on osteoporosis.

RESULTS

BMSCs-Exos were internalized by THP-1 cells, promoted YAP1 expression and autophagy, and inhibited osteoclast differentiation. Silencing of YAP1 in THP-1 cells reversed BMSCs-Exos-induced autophagy and the inhibition of osteoclast differentiation; conversely, YAP1 overexpression produced opposite effects. BMSCs-Exos-delivered RBM15B promoted m6A methylation modification of YAP1. Silencing of RBM15B in BMSCs blocked the impact of BMSCs-Exos on autophagy and osteoclast differentiation, whereas RBM15B overexpression exerted opposing influences. Furthermore, BMSCs-Exos suppressed osteoclast differentiation and alleviated osteoporosis in vivo through RBM15B/YAP1 mediated autophagy.

CONCLUSIONS

BMSCs-Exos promoted m6A methylation modification of YAP1 by delivering RBM15B mRNA to enhance YAP1 RNA stability, promoted autophagy, and inhibited osteoclast differentiation and alleviated osteoporosis.