Journal of Osteoporosis and Physical Activity
Open Access

Abstract

Mouse Genetics Studies on Molecular Mechanisms Underlying Skeletal Disorders

Hiroshi Kawaguchi

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.