Mouse Genetics Studies on Molecular Mechanisms Underlying Skeletal Disorders

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.