Abstract
Type 2 diabetes (T2D) is a significant and growing public health concern, currently affecting more than 460 million people worldwide. People with T2D have a higher risk of bone fracture despite having normal-to-high bone mineral densities. Therefore, the increased fragility experienced by type 2 diabetics may be the result of changes to bone quality. Our goal is to investigate potential molecular and cellular mechanisms affecting bone quality under diabetic conditions. At the molecular level, the accumulation of advanced glycation end-products (AGEs), or harmful crosslinks in between collagen fibers, can embrittle the collagen matrix and cause deterioration of bone tissue. One fluorescent AGE, pentosidine, has previously been measured in urine and plasma and was found to accumulate to greater levels in cases of diabetes. We developed a high-performance liquid chromatography (HPLC) method to measure pentosidine in human bone specimens from four donors with distinct ages and disease states. The results show old age and T2D status to be associated with higher bone pentosidine content. In young donors, T2D corresponded to a higher pentosidine concentration and weaker bone mechanical properties compared to the non-diabetic control, suggesting a negative relationship between pentosidine levels and fracture toughness. At the cellular level, bone fragility can be caused by reduced bone turnover and loss of bone cells, both of which are experienced by people with T2D. Therefore, our second aim was to investigate how a diabetic environment affects the regulation of the bone remodeling process. Osteocytes cultured with pentosidine and high glucose demonstrated increases in the expression of genes associated with elevated bone resorption and the inhibition of bone formation compared to controls. Overall, the accumulation of pentosidine and subsequent alterations to gene expression may be key contributors to the decreased bone quality and high fracture risk of people with T2D.