β-Sitosterol modulates osteogenic and adipogenic balance in BMSCs to suppress osteoporosis via regulating mTOR-IMP1-Adipoq axis.

Background: Osteoporosis (OP) is a prevalent global health concern, impacting millions of individuals, especially the elderly. The etiology of senile OP is associated with the imbalance of osteogenic and adipogenic differentiation in the bone marrow mesenchymal stem cells (BMSCs). The imbalance of BMSCs differentiation fate will leading to bone loss and lipids accumulation. β-sitosterol, a naturally occurring phytosterol which is abundant in plants and has a similar structure to cholesterol, demonstrates diverse bioactivities, including lipid-lowering effect and osteogenesis-inducing effects. These effects indicate that β-sitosterol might have anti-OP effects. Nevertheless, the precise mechanism underlying β-sitosterol's anti-osteoporotic efficacy via modulating BMSCs differentiation fate remains obscure.

Purpose: This study endeavors to elucidate whether β-sitosterol has the potential to augment the osteogenic differentiation of BMSCs while mitigating their adipogenic differentiation, thereby exerting an anti-OP effect; and to reveal its molecular mechanisms of action.

Methods: In this study, a dosage form HP-β-cyclodextrin-coated β-sitosterol was developed for intragastric administration in mice to enhancing its bioavailability. Subsequently by using an integrative approach encompassing bioinformatics, computer molecular simulations, high-throughput sequencing, and in vitro/vivo as well as in-tube experiments, we investigated the anti-osteoporotic and bone healing effects of β-sitosterol and delineated its underlying mechanisms.

Results: Our findings demonstrate that β-sitosterol exhibits anti-osteoporotic and bone healing effects both in vitro and in vivo by modulating the osteogenic and adipogenic differentiation of BMSCs. Mechanistically, these effects are mediated through the direct inhibition of mTOR's kinase activity independent of mediating autophagy, leading to the suppression of the mTOR-IMP1-Adipoq axis in BMSCs.

Conclusion: These results unveil β-sitosterol as a promising therapeutic agent for OP, shedding light on its underlying mechanisms. This research contributes potential candidates for diagnostic and therapeutic interventions in the realm of OP.