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Advanced glycation end products mediate biomineralization disorder in diabetic bone disease

Qianmin Gao,Yingying Jiang,Dongyang Zhou,Guangfeng Li,Yafei Han,Jingzhi Yang,Ke Xu,Yingying Jing,Long Bai,Zhen Geng,Hao Zhang,Guangyin Zhou,Mengru Zhu,Ning Ji,Ruina Han,Yuanwei Zhang,Zuhao Li,Chuandong Wang,Yan Hu,Hao Shen,Guangchao Wang,Zhongmin Shi,Qinglin Han,Xiao Chen,Jiacan Su

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.