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

Exercise significantly enhances bone mass. However, whether exercise can alter the bone microenvironment through exosomes and the underlying molecular mechanisms remains unclear. 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. In this study, 18-month-old male mice were subjected to 8 weeks of treadmill exercise for 1 h daily. Changes in bone mass were assessed using micro-computed tomography (micro-CT), real-time polymerase chain reaction (RT-PCR), hematoxylin and eosin (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, and alkaline phosphatase (ALP) and alizarin red S (ARS) staining. 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 yes-associated protein (YAP1) and promoting the nuclear translocation of β-catenin. Inhibition of miR-206 abolished the exercise-induced improvements in bone mass. 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.