Asperosaponin VI ameliorates osteoporosis via skeletal muscle-derived FGF-2-mediated osteoblast differentiation.

BACKGROUND

Skeletal muscle functions as a dynamic endocrine organ, secreting myokines that contribute to systemic physiological homeostasis. Despite the established osteoprotective effects of Asperosaponin VI (AVI), it remains unknown whether these effects are mediated via the modulation of muscle-derived factors that subsequently regulate bone metabolism.

PURPOSE: The present study aims to investigate whether AVI alleviates ovariectomy (OVX)-induced bone loss by modulating muscle-derived signals that exert regulatory effects on osteogenesis.

METHODS

Female C57BL/6 OVX mouse models and the co-culture system composed of AVI-treated myotubes and osteoblasts were used. The bone structural microarchitecture, muscle phenotypic changes, bone formation markers were analyzed. Transcriptomics, molecular docking, and cellular thermal shift assays (CETSA) were performed to uncover the core targets and the potential mechanisms involved.

RESULTS

AVI significantly improved both trabecular and cortical bone structures in OVX mice, which were associated with simultaneous upregulation of osteogenesis and inhibition of osteoclast activity, along with induction of a phenotypic shift from fast- to slow-twitch muscle fiber types. In vitro studies found that treatment with AVI in myotubes remarkably increased osteogenesis through paracrine action. Mechanistically, AVI bound to and stabilized the transcription factor early growth response 1 (EGR-1) in muscle cells to facilitate rapid EGR-1 nuclear translocation, thus leading to secretion of fibroblast growth factor-2 (FGF-2). Moreover, the key effectors identified in the gene expression profiling, namely fibroblast growth factor receptor 1 (FGFR1), were proven to be required for activation of the osteoblastic Wnt/β-catenin signaling pathway downstream FGF-2.

CONCLUSIONS

The present work revealed AVI as an effective therapy in treating post-menopause osteoporosis through direct modulation of EGR-1 in muscle cells to enhance FGF-2 secretion that activated osteoblastic Wnt/β-catenin signaling via FGFR1.