Molecular backgrounds of age-related osteoporosis from mouse genetics approaches.
Backgrounds underlying age-related bone loss can be classified into two categories: systemic abnormality and osteoblast dysfunction. The former includes insufficiency of vitamin D or estrogen, causing a negative balance of calcium metabolism. We propose the contribution of an aging-suppressing gene, klotho, as a novel systemic factor, as a mouse deficient in the klotho gene exhibits multiple aging phenotypes including osteopenia with a low bone turnover. As a factor intrinsic to osteoblasts, we investigated the role of PPARgamma, a key regulator of adipocyte differentiation, based on the facts that osteoblasts and adipocytes share a common progenitor. Heterozygous PPARgamma-deficient mice exhibited high bone mass by stimulating osteoblastogenesis from bone marrow progenitors, and this effect became prominent with aging, indicating involvement of PPARgamma-dependent bone formation in the pathophysiology of age-related bone loss. The local environment of osteoblasts is mainly controlled by cytokines/growth factors, among which insulin-like growth factor-I (IGF-I) is the most possible candidate whose production and activity are decreased with aging. Bone phenotypes of deficient mice of insulin receptor substrates (IRS-1 and IRS-2), essential molecules for intracellular signaling of IGF-I, revealed that IRS-1 is essential to maintain bone turnover by up-regulating anabolic and catabolic functions of osteoblasts, while IRS-2 is needed to keep the predominance of the anabolic function over the catabolic function. A next task ahead of us will be to elucidate the network system of these factors underlying age-related osteoporosis.
Kawaguchi
Hiroshi
H
Department of Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan. kawaguchi-ort@h.u-tokyo.ac.jp
D000818:Animals; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000235:genetics / Q000502:physiology; D000090265:Klotho Proteins; D051379:Mice; D008954:Models, Biological; D010024:Osteoporosis / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011972:Receptor, Insulin; D015398:Signal Transduction
D047495:PPAR gamma; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; C081827:insulin receptor serine kinase; D005966:Glucuronidase; D000090265:Klotho Proteins