Abstract
Backgrounds underlying the 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 ageing-suppressing gene, klotho, as a novel systemic factor, since the 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 PPARγ-deficient mice exhibited high bone mass by stimulating osteoblastogenesis from bone marrow progenitors, and this effect became prominent with ageing, indicating involvement of PPARγ-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 ageing. 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 the age-related osteoporosis.
Highlights
Backgrounds underlying the age-related bone loss can be classified into two categories: systemic abnormality and osteoblast dysfunction
This review summarizes the possible roles of three different types of molecules, a hormone klotho, an osteoblast intrinsic factor peroxisome proliferatoractivated receptor-γ (PPARγ), and a local factor insulin-like growth factor-I (IGF-I) by way of its adaptor molecule insulin receptor substrates (IRS), in age-related bone loss primarily from our recent mouse genetics approaches
We investigated the physiological role of PPARγ in bone metabolism [35], using heterozygous PPARγ-deficient (PPARγ+/-) mice [36]
Summary
There are three major backgrounds of osteoporosis in aged women: 1) the peak bone mass during their adolescence was low, 2) the bone loss by menopause due to estrogen deficiency was severe, and 3) the bone loss by ageing thereafter was severe (Figure 1); each of these has an independent mechanism. Regarding the mechanisms underlying the bone loss by ageing, accumulated evidence has suggested many age-related abnormalities which can be classified into two categories: systemic abnormality and osteoblast dysfunction (Figure 2) The former includes insufficiency of active vitamin D or estrogen, which decreases calcium absorption from G.I. and kidney, causing a negative balance of calcium metabolism and a secondary hyperparathyroidism [1,2,3,4,5,6,7,8]. The latter can be further divided into abnormalities that occur inside and outside of osteoblasts. To further investigate its molecular backgrounds, we have been involved
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