Molecular backgrounds of agerelated osteoporosis

Authors: Hiroshi Kawaguchi

Publish Date: 2006/11/23

Volume: 7, Issue: 1-2, Pages: 17-22

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Abstract

Backgrounds underlying agerelated 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 agingsuppressing 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 PPARγ a key regulator of adipocyte differentiation based on the facts that osteoblasts and adipocytes share a common progenitor Heterozygous PPARγdeficient mice exhibited high bone mass by stimulating osteoblastogenesis from bone marrow progenitors and this effect became prominent with aging indicating involvement of PPARγdependent bone formation in the pathophysiology of agerelated bone loss The local environment of osteoblasts is mainly controlled by cytokines/growth factors among which insulinlike growth factorI IGFI is the most possible candidate whose production and activity are decreased with aging Bone phenotypes of deficient mice of insulin receptor substrates IRS1 and IRS2 essential molecules for intracellular signaling of IGFI revealed that IRS1 is essential to maintain bone turnover by upregulating anabolic and catabolic functions of osteoblasts while IRS2 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 agerelated osteoporosis

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