Involvement of Lipid and Glucose Metabolism in Skeletal Disorders of Animal Models

Degenerative skeletal diosrders are now considered a major public health issue causing chronic disability in most developed countries. This paper summarizes our mouse genetics studies on the molecular backgrounds of representative degenerative skeletal diosrders: osteoporosis, Ossification of the Posterior Longitudinal Ligament of the Spine (OPLL), and bone fracture healing. By analyzing deficient mice, PPARγ, a key adipogenesis molecule intrinsic to bone marrow progenitors, was shown to be involved in age-related osteoporosis. Studies on deficient mice and OPLL patients revealed that insulin and insulin-like growth factor-I (IGF-I) are potent bone anabolic factors through the balance of distinct signals of the two adaptor molecules, Insulin Receptor Substrate (IRS)-1 and IRS-2: IRS-1 for maintenance of bone turnover by up-regulating anabolic and catabolic functions of osteoblasts, while IRS- 2 for retaining the predominance of the anabolic function over the catabolic function. IRS-1 was also essential for bone fracture healing. These molecules could be therapeutic targets for the skeletal disorders. Although we used the mouse genetics approaches, we have attempted to confirm the reproducibility of the mouse findings in humans using human gene polymorphism or clinical biochemical studies. Among the molecules we identified in this study, there are some whose suppression ameliorated skeletal disorders under pathological conditions but did not affect physiological conditions, indicating that targeting on these molecules may lead to an ideal treatment without side effects on physiological functions. In fact, trials based on the present findings are being practically planned for clinical application.