Exercise-intervened BMSC exosomes promote osteogenesis and alleviate aging-induced bone loss via YAP1/β-catenin signaling pathway

Background: Exercise significantly enhances bone mass, however, whether exercise can alter the bone microenvironment through exosomes and the underlying molecular mechanisms remain unclear.

Objectives: This study aims to investigate the role of exercise in mitigating osteoporosis and to elucidate the molecular mechanisms of exercise-intervened bone marrow mesenchymal stromal cells (BMSCs) exosomes in the treatment of osteoporosis.

Methods: In this study, 18-month-old male mice were subjected to 8 weeks of treadmill exercise for 1 hour daily. Changes in bone mass were assessed using micro-CT, RT-PCR, H&E, calcein, immunohistochemistry, and immunofluorescence staining. The distribution and therapeutic effects of exosomes on osteoporosis were evaluated using immunofluorescence staining and small-animal imaging systems. Finally, the molecular mechanisms by which BMSC-derived exosomes regulate bone mass were explored through RNA sequencing, PCR, luciferase assays, ALP and ARS staining.

Results: Exercise alleviated the symptoms of bone loss through an increase in the number of osteoblasts and type H vessels. Blocking exosome release from BMSCs significantly reversed exercise-induced improvements in bone mass. Furthermore, exercise-intervened BMSCs exosomes could promote osteoblast differentiation and effectively target bone and ameliorate osteoporosis induced by aging. Mechanistically, miR-206 was found to regulate osteoblast differentiation by binding to YAP1 and promoting the nuclear translocation of β-catenin. Inhibition of miR-206 abolished the exercise-induced improvements in bone mass.

Conclusions: This study demonstrates that exercise-intervened BMSCs exosomes can alleviate osteoporosis by delivering miR-206 to regulate the YAP1/β-catenin pathway. These findings provide new insights into the mechanisms by which exercise ameliorates osteoporosis and offer potential therapeutic strategies for future osteoporosis treatments.