Endothelial cell-derived exosomes: A natural shield against osteoblast ferroptosis in diabetes

Abstract

In this editorial, we discuss a significant recent study published in World Journal of Diabetes by Shao et al. Diabetic osteoporosis (DOP) is a severe skeletal complication of diabetes. Emerging evidence indicates that ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in osteoblast dysfunction and bone loss under hyperglycemic conditions. However, the precise mechanisms through which osteoblast ferroptosis can be effectively targeted for the treatment of diabetic osteopenia remain elusive. The study by Shao et al advances our understanding of DOP by demonstrating that endothelial cell-derived exosomes function as a natural delivery system that protects osteoblasts from high glucose-induced ferroptosis. The authors identify microRNA-335-3p (miR-335-3p) as the key molecular mediator within this protective mechanism, acting by directly targeting and suppressing prostaglandin endoperoxide synthase 2, a recognized marker of ferroptosis. Clinically, an inverse correlation was observed between serum miR-335-3p levels and disease severity, highlighting that miR-335-3p not only represents a potential therapeutic target but also a promising non-invasive biomarker for early detection and monitoring of DOP, thereby underscoring its translational relevance.

Keywords: Diabetic osteoporosis; Endothelial cell-derived exosomes; Ferroptosis Prostaglandin endoperoxide synthase 2; microRNA-335-3p; Bone mineral density

Core Tip: Diabetic osteoporosis (DOP), a common diabetic complication lacking targeted treatments, stems from chronic hyperglycemia disrupting the bone microenvironment. Key pathophysiological mechanisms include the accumulation of advanced glycation end products, oxidative stress, inflammation, and cell death. Currently, the field of DOP is moving beyond bone mineral density to understand the molecular and cellular dysregulation at the bone-vascular interface, aiming for precise diagnostics and therapies. This editorial highlight endothelial cell-derived exosomes and their cargo microRNA-335-3p as emerging and critical players in the pathophysiology of DOP. It discusses their role in inhibiting osteoclast ferroptosis and alleviating bone loss, while also identifying serum microRNA-335-3p as a promising non-invasive biomarker for early detection and monitoring, bridging molecular mechanisms with clinical translation.