ABSTRACTTYPE I DIABETIC OSTEOPOROSIS AND OSTEOBLAST APOPTOSIS ByLindsay Martin CoeType I diabetes is a metabolic disorder that affects roughly 1 million people in the United States. Medical advances are lengthening patient lifespan resulting in longer exposure to hyperglycemia causing secondary complications including bone loss. Bone formation and density are decreased in T1-diabetic mice. During diabetes onset, levels of blood glucose and pro-inflammatory cytokines (including tumor necrosis factor alpha (TNFalpha)) are increased. I hypothesized that early diabetes onset can promote osteoblast death resulting in diabetic bone loss. Indeed, examination of type I diabetic mouse bones demonstrates a greater than 2-fold increase in osteoblast TUNEL staining and increased expression of pro-apoptotic factors. Osteoblast death was amplified in both pharmacologic and spontaneous diabetic mouse models. Co-culture studies demonstrate that diabetic bone marrow cells increase osteoblast caspase 3 activity and Bax:Bcl-2 RNA ratio. Administration of TNF-neutralizing antibody prevented diabetic marrow-induced osteoblast death. Several apoptotic mechanisms could account for this increase in osteoblast death. Two known mediators of osteoblast death, TNFalpha and ROS, are increased in T1-diabetic bone. TNFalpha; and oxidative stress are known to activate caspase-2, a factor involved in the extrinsic apoptotic pathway. This dissertation determines that caspase-2 is not required for diabetes-induced osteoblast death or bone loss indicating another apoptotic factor is sufficient. Bax, a pro-apoptotic factor that mediates the intrinsic death pathway is also elevated in T1-diabetic bone. Deficiency of Bax results in protection against diabetes-induced osteoblast death and decreased bone density. Targeting osteoblast apoptosis is a possible therapeutic strategy for preventing diabetes-induced osteoporosis. One commonly used treatment against osteoporosis is bisphosphonates. Here I demonstrate that bisphosphonate therapy prevents diabetes-induced osteoblast death and bone loss. Furthermore, diabetes induced bone marrow inflammation can also contribute to osteoblast death and is another potential therapeutic target for inhibiting osteoporosis. Administration of the non-steroidal anti-inflammatory drug, aspirin, resulted in enhanced bone formation markers and decreased diabetic hyperglycemia, but did not protect against diabetic bone loss. This dissertation focuses on the relevance of osteoblast apoptosis and bone marrow inflammation as two potential mediators of diabetes-induced bone loss and addresses two commonly used therapies as preventive treatments for T1-diabetes-induced osteoporosis.
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