Role of oxidative stress in diabetic bone disorder.

Diabetes mellitus induces alterations in bone and mineral metabolism. Diabetic bone disorder causes an increase in bone fractures, delays healing of fractures, and affects the quality of life. There are few optimal therapies for these disorders and the mechanisms responsible for their complications have not been clearly identified. Bone histology studies in humans and animals have demonstrated that decreased bone formation is a critical mechanism of bone mass reduction in diabetes. A major hypothesis about the mechanisms of diabetic complications is a diabetes-induced increase in oxidative stress, because reactive oxygen species (ROS) are increased under diabetic conditions and are known to induce cellular dysfunction in a wide variety of cell types. Oxidative stress is induced by a variety of mechanisms including formation of increased advanced glycation end-products (AGEs), increased polyol pathway flux, activation of protein kinase C isoforms, glucose autoxidation, and mitochondrial overproduction of superoxide under diabetic conditions. Other circulating factors that are elevated in diabetes, such as free fatty acids and leptin, also contribute to increased ROS generation. It is now widely accepted that ROS can cause severe damage to DNA, proteins, and lipids. Concerning bone metabolism, in vitro studies have shown that oxidative stress inhibits osteoblastic differentiation and induces osteoblast insults and apoptosis. Moreover, we have demonstrated that both streptozotocin-induced diabetic mice, an animal model of type 1 diabetes, and spontaneously diabetic Torii (SDT) rats, an animal model of type 2 diabetes, have low-turnover osteopenia associated with increased oxidative stress and that markers of oxidative stress are inversely associated with the histomorphometric parameters of bone formation. Growing evidence suggests that the increase in oxidative stress may at least partly contribute to the development of diabetic osteopenia. This review focuses on the impact of diabetes-induced oxidative stress in the development of diabetic bone disorder.