SAT-176 Cellular Mechanisms of Impaired Bone Remodeling in Type 1 Diabetes Mellitus

Abstract

Type 1 Diabetes Mellitus (T1DM) is one of the most common chronic diseases in childhood, with a mean age of ~14 years at diagnosis. Coincidentally, this is also the time peak bone accrual occurs. T1DM subjects show reductions in bone mineral density, which are sustained through adulthood, leading to a high risk for fracture. The cause for reduced BMD in T1DM is not fully understood but is thought to result from suppressed bone turnover. Surprisingly, despite their abundance in bone and their critical importance in regulating bone remodeling, little attention has been given to osteocytes and their response to chronic hyperglycemia. We hypothesize that osteocytes of diabetic NOD mice index cumulative metabolic stress that affects their regulation of bone remodeling. To test our hypothesis we used the non-obese diabetic (NOD) mouse as a model for T1DM. We grouped the NOD mice according to the severity of the disease (no diabetes, moderate and severe diabetes) and studied the effects of T1DM on skeletal morphology by micro-computed tomography (mCT) and bone histomorphometry. Additionally we established primary osteoblasts, osteoclasts, and osteocytes cultures from NOD mice. mCT data showed that NOD mice with severe diabetes exhibited reductions in cortical bone, total cross sectional area, and cortical bone thickness as compared to NOD mice with moderate diabetes or NOD mice with sporadic increases in blood glucose that did not develop full blown diabetes. Histomorphometry of cortical bone at the femur mid-diaphysis revealed complete inhibition of bone formation and mineral apposition rates in the diabetic mice. These data is associated with reduced alkaline-phosphatase positive cells in primary osteoblast cultures, suggesting reductions in osteoprogenitor numbers in diabetic NOD mice. Primary osteocyte cultures from diabetic NOD mice revealed impaired mitochondrial function, which likely contributes to the impaired bone remodeling. Overall, we show significant impairments in bone remodeling in diabetic NOD mice, which results not only from impaired osteoblast function but also from dysfunction of osteocytes. Future studies will focus on the contribution of osteocyte to bone remodeling in T1DM.