Advanced glycation end products mediate biomineralization disorder in diabetic bone disease

Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD. • Advanced glycation end products (AGEs) disrupt biomineralization in diabetic bone • AGEs increase non-enzymatic crosslinking of COL1, blocking mineralization • Guanidines inhibit AGEs, improving bone quality in diabetes • Targeting AGEs offers a therapeutic strategy to enhance diabetic bone health Gao et al. explore the therapeutic implication and underlying mechanism of diabetic bone paradox (DBP). They demonstrate that advanced glycation end products (AGEs) disrupt collagen fibril mineralization in diabetic bones by promoting non-enzymatic crosslinking.