Hyperoside promotes osteoblast differentiation by increasing osteoclast-derived migrasomes to alleviate osteoporosis

Osteoporosis, resulting from an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, can be alleviated by hyperoside. Migrasomes, as newly discovered extracellular vesicles, play a crucial role in mediating intercellular communication. However, it remains unclear whether hyperoside alleviates osteoporosis by mediating intercellular communication between osteoblasts and osteoclasts through migrasomes. This study investigates the potential therapeutic mechanisms of hyperoside in treating osteoporosis using an ovariectomized mouse model.

Hyperoside was administered to the mice by intragastric gavage daily for 2 months. Micro-CT scans and histopathological analyses were performed to evaluate bone formation. Migrasomes derived from hyperoside-treated osteoclasts were characterized by transmission electron microscopy, Western blot, and immunofluorescence, and subsequently used to treat osteoblasts followed by RNA sequencing.

Micro-CT scans and histopathological evaluations showed that hyperoside reduced bone resorption and osteoclast numbers in ovariectomized mice. Immunofluorescence staining revealed that hyperoside increased the expression of osteoblast regulators OPG and RUNX2. Hyperoside increased migrasome secretion from osteoclasts, which was validated by transmission electron microscopy and Western blot analyses. Migrasomes were then used to treat MC3T3-E1 cells, boosting osteoblast marker expressions and differentiation. RNA sequencing of migrasomes showed distinct regulatory patterns, with upregulated genes in the hyperoside-treated migrasomes compared to the control linked to immune responses, iron ion homeostasis, oxidative stress, and apoptosis, and downregulated genes related to lipid metabolism. Notably, hyperoside-regulated migrasomes also affected ferroptosis by increasing ferroptosis repressors Nr4a1, Lcn2, Nupr1, and Zfp36.

These findings suggest that hyperoside exerts its osteogenic effects through migrasome-mediated crosstalk, offering new insights into the treatment of osteoporosis.