Paracrine activity of Smurf1-silenced mesenchymal stem cells enhances bone regeneration and reduces bone loss in postmenopausal osteoporosis

• Smurf1-silenced MSC secretome significantly enhances in vitro mineralization and in vivo bone formation, with effects comparable to BMP2 treatment. • The secretome reduces RANKL expression without affecting OPG levels, indicating a potent anti-resorptive effect in human bone explants. • A single local administration of the secretome reduced trabecular bone loss by 50% in a postmenopausal osteoporotic mouse model within four weeks. • Proteomic analysis identified key proteins in the secretome that promote ossification and extracellular matrix organization, supporting its therapeutic potential as a cell-free treatment for osteoporosis.