This paper summarizes 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.
Ageing is one of the major causes of osteoporosis, and the underlying mechanisms include intracellular and extracellular signals of osteoblastic cells. As an intracellular molecule regulating age-related osteoporosis, Runx2, a key transcription factor for osteoblast differentiation, is the most probable candidate, since the expression is reported to be decreased during cellular ageing of osteoblasts in vitro. However, there is no in vivo evidence of its contribution to bone loss with ageing.