Schwann cell-derived extracellular vesicles inhibit osteoclastogenesis through the PTEN/AKT axis in peripheral nerve-bone crosstalk

Osteoclasts, the sole bone-resorbing cells, play a central part in bone homeostasis, and their overactivation is implicated in bone diseases such as osteoporosis. Schwann cells (SCs), the primary glial cells of the peripheral nervous system, are recognized to contribute to participating in bone remodeling through interactions with osteoblasts. Nevertheless, their specific function in osteoclasts-mediated bone resorption remains to be fully elucidated. Here, we demonstrate that SCs inhibit osteoclastogenesis in bone homeostasis, primarily through extracellular vesicles (EVs)-mediated activation of PTEN, which in turn negatively regulates the PI3K/AKT signaling pathway, and consequently attenuates the bone resorption process. To promote the targeted delivery and accumulation of EVs in bone tissue, SC-derived EVs (SC-EVs) were engineered with acidic peptides. Subsequent studies in vivo revealed that EVs derived from SCs significantly mitigated bone loss in ovariectomized mice, and bone-targeted EVs exhibited superior efficacy in restoring bone mass. These findings elucidated the neural regulation of bone homeostasis and proposed that SC-EVs, as peripheral nerve-bone crosstalk, could become a novel therapeutic approach for osteoporosis. In vitro, Schwann cell-derived extracellular vesicles (SC-EVs) inhibit osteoclastogenesis of bone marrow macrophages (BMMs) through the PTEN/AKT signaling pathway, thereby attenuating bone loss. Bone-targeted EVs derived from SCs (SC-BTEVs), engineered with acidic peptides, possess bone-targeting capability and exert stronger inhibitory effects against osteoporosis compared to SC-EVs in an ovariectomized (OVX) mouse model via the same signaling pathway.