Pathogenesis and treatment of type 1 diabetic osteoporosis

Type 1 diabetes (T1-diabetes) is a chronic condition characterized by hypoinsulinemia and hyperglycemia. Patients with T1-diabetes are susceptible to complications, including osteoporosis. Bone loss from diabetes increases risk of fracture and impairs fracture healing. Understanding the mechanism of diabetic osteoporosis is important for choosing the best therapies. Reduced bone formation (not altered resorption) is responsible for diabetic bone loss. Additionally, rodent models of T1-diabetes (streptozotocin and the non-obese diabetic mouse) have increased marrow adipocyte number compared normal, suggesting mesenchymal stem cell lineage selection favors the osteoblast over the adipocyte in diabetic conditions. In Chapter 2, we characterized the bone phenotype of mice during diabetes induction and found that markers of osteoblasts and adipocytes were altered as early as two days after blood glucose levels began to rise. Because diabetes is associated with inflammation, we measured serum and bone pro-inflammatory cytokine levels and found increases in cytokines that coincided with reduced osteoblast activity. Diabetes is also associated with reduced serum leptin, a hormone secreted by adipocytes that is capable of promoting bone formation in conditions of unloading. In Chapter 3, we treated diabetic mice with leptin and found that chronic subcutaneous leptin infusion prevented diabetic marrow adiposity but not bone loss, suggesting that marrow adiposity is not required for diabetic osteoporosis. In Chapter 4, we induced diabetes in mice lacking CCAAT/enhancer binding protein beta (C/EBPbeta), a transcription factor that promotes adiposity and prevents osteoblast differentiation. We found that under diabetic conditions, the lack of C/EBPbeta actually enhanced adipocyte differentiation in bone and increased bone resorption, which is not classically observed in T1-diabetes. In Chapter 5, we found reduced Wnt10b, a strong activator of osteoblast differentiation and inhibitor of adipogenesis, in diabetic bone. To test whether Wnt10b was a factor influencing bone changes in diabetes, we induced T1-diabetes in mice with overexpression of Wnt10b in osteoblasts. Wnt10b mice were protected from bone loss but not marrow adiposity in diabetes. Finally, in Chapter 6 we examined the ability of intermittent parathyroid hormone (PTH), the only anabolic osteoporosis therapy available to patients, to promote bone formation in diabetes. We found that PTH increased osteoblast maturation and prevented osteoblast death, even under diabetic conditions. Bone density levels of diabetic mice returned to those of untreated controls, even after bone loss had already occurred. Taken together, Chapters 2--5 demonstrate that bone marrow fat is likely not necessary for diabetic bone loss. Additionally, Chapter 5 and 6 suggest that anabolic therapies targeting Wnt10b/wnt signaling could improve bone density in diabetic patients.