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.

The excessive reactive oxygen species (ROS) accumulation and overactivated osteoclastogenesis in subchondral bone has proved to be a major cause of osteoarthritis (OA). Scavenging of ROS microenvironment to inhibit the osteoclastogenesis is highly valued in the therapeutic process of osteoarthritis. Despite the excellent ability of polyphenolic colloidal to scavenge reactive oxygen species and its affinity for macrophages, the preparation of polyphenolic colloidal nanoparticles is limited by the complex intermolecular forces between phenol molecules and the lack of understanding of polymerization/sol-gel chemistry. Herein, our work introduces a novel poly-tannin-phenylboronic colloidal nanoparticle (PTA) exclusively linked by ROS-responsive bondings. Nanocolloidal PTA has a uniform particle size, is easy and scalable to synthesize, has excellent scavenging of ROS, and can be slowly degraded. For in vitro experiments, we demonstrated that, PTA could eliminate ROS within RAW264.7 cells and impede osteoclastogenesis and bone resorption. RNA sequencing results of PTA-treated RAW264.7 cells further reveal the promotion of antioxidant activity and inhibition of osteoclastogenesis. For in vivo experiments, PTA could eliminate the ROS environment and reduce the number of osteoclasts in the subchondral bone, thereby alleviating the damage of subchondral bone and symptoms of osteoarthritis. Our research, by delving into the formation of polyphenol colloidal nanoparticles and validating their role in ROS scavenging to inhibit osteoclastogenesis in subchondral bone, may open new avenues for OA treatment in the future.