Molecular backgrounds of age-related osteoporosis from mouse genetics approaches
Molecular backgrounds of age-related osteoporosis from mouse genetics approaches
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DOI：
10.1007/s11154-006-9011-3
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发表时间：
2006-06-01
影响因子：
8.2
通讯作者：
Kawaguchi, Hiroshi
中科院分区：
文献类型：
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作者：
Kawaguchi, Hiroshi
背景与年龄相关的骨质流失可分为两类：系统性异常和成骨细胞功能障碍。前者包括维生素D或雌激素不足，导致钙代谢负平衡。我们提出衰老抑制基因klotho作为一种新的系统因子的贡献，因为缺乏klotho基因的小鼠表现出多种衰老表型，包括骨质减少和低骨转换。作为成骨细胞的内在因子，我们基于成骨细胞和脂肪细胞具有共同的祖细胞这一事实，研究了脂肪细胞分化的关键调节因子PPAR γ的作用。杂合子PPAR γ缺失小鼠通过刺激骨髓祖细胞的成骨细胞生成而表现出高骨量，并且随着年龄的增长，这种作用变得突出，表明PPAR γ依赖性骨形成参与了与年龄相关的骨质流失的病理生理学。成骨细胞的局部环境主要受细胞因子/生长因子控制，其中胰岛素样生长因子- i （IGF-I）是最有可能的候选者，其产量和活性随着年龄的增长而下降。胰岛素受体底物（IRS-1和IRS-2）是IGF-I细胞内信号传递的必需分子，其缺失小鼠的骨表型显示，IRS-1通过上调成骨细胞的合成代谢和分解代谢功能来维持骨转换，而IRS-2则需要保持合成代谢功能优于分解代谢功能。摆在我们面前的下一个任务将是阐明这些与年龄有关的骨质疏松症的潜在因素的网络系统。
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 PPAR gamma, a key regulator of adipocyte differentiation, based on the facts that osteoblasts and adipocytes share a common progenitor. Heterozygous PPAR gamma-deficient mice exhibited high bone mass by stimulating osteoblastogenesis from bone marrow progenitors, and this effect became prominent with aging, indicating involvement of PPAR gamma-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.