1‐Deoxynojirimycin Alleviates Osteoporosis via Promoting LRP5 Signaling in Osteoblasts and BMSCs

Osteoporosis is the most common bone disease worldwide, and natural bioactive products that promote osteogenesis are a therapeutic strategy to prevent osteoporosis. 1-Deoxynojirimycin (DNJ) is the major bioactive small molecule in mulberry with anti-diabetic properties, but its effect on osteoporosis treatment remains largely unexplored. This study aims to investigate the effects and underlying mechanisms of DNJ on osteoporosis, with a particular emphasis on its ability to promote osteogenesis pathways. We investigated the bone anabolic ability of DNJ in two well-recognized osteoporosis models: ovariectomy-induced and high-fat diet (HFD)-induced osteoporosis. DNJ prevented estrogen deficiency and HFD-induced bone loss, resulting in increased osteoblast number and inhibited osteoclast number, supporting its therapeutic potential for osteoporosis. Consistent with these in vivo results, in vitro experiments showed that DNJ promoted osteogenic differentiation and matrix mineralization of primary BMSCs and osteoblasts without affecting primary osteoclast differentiation. Mechanistic studies revealed that DNJ increased osteoblastic mineralization by directly binding to the extracellular domain of the transmembrane protein LRP5, thus promoting the Wnt/β-catenin signaling axis to activate the transcription of osteogenesis-related genes in osteoblasts. Taken together, our study demonstrated that DNJ plays a critical role in activating the LRP5/β-catenin pathway, suggesting its potential as a candidate for osteoporosis prevention and treatment.