Insulin receptor substrate-1 in osteoblast is indispensible for maintaining bone turnover
Insulin receptor substrate-1 in osteoblast is indispensible for maintaining bone turnover
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DOI：
10.1172/jci9017
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发表时间：
2000-04-01
影响因子：
15.9
通讯作者：
Kawaguchi, H
中科院分区：
文献类型：
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作者：
Ogata, N;Chikazu, D;Kawaguchi, H
胰岛素受体底物（IRS-1和-2）对胰岛素和igf -1的细胞内信号传导至关重要，igf -1是骨代谢的合成代谢调节因子。缺乏IRS-1基因IRS-1（-/-）的小鼠表现出严重的骨质减少和低骨转换。IRS-1在野生型（WT）小鼠的成骨细胞中表达，而在破骨细胞中不表达。胰岛素或IGF-I处理的IRS-1（-/-）成骨细胞不能诱导细胞蛋白的酪氨酸磷酸化，它们表现出增殖和分化减少。造血细胞与成骨细胞共培养时，破骨细胞的形成依赖于成骨细胞中IRS-1的表达，在igf -1和1,25(OH)(2)D-3存在的情况下，造血细胞中IRS-1的表达不能拯救破骨细胞。此外，这些因子在IRS-1（-/-）成骨细胞中未诱导破骨细胞分化因子（RANKL/ODF）。我们得出结论，成骨细胞中IRS-1的缺乏会损害成骨细胞的增殖、分化和对破骨细胞形成的支持，导致低周转率骨质减少。成骨细胞IRS-1对于维持骨转换至关重要，因为它介导igf -1和胰岛素的信号传导，我们提出，也介导其他因素，如1,25(OH)(2)D-3。
Insulin receptor substrates (IRS-1 and -2) are essential for intracellular signaling by insulin and IGF-I, anabolic regulators of bone metabolism. Mice lacking the IRS-1 gene IRS-1(-/-) showed severe osteopenia with low bone turnover. IRS-1 was expressed in osteoblasts, but not in osteoclasts, of wild-type (WT) mice. IRS-1(-/-) osteoblasts treated with insulin or IGF-I failed to induce tyrosine phosphorylation of cellular proteins, and they showed reduced proliferation and differentiation. Osteoclastogenesis in the coculture of hemopoietic cells and osteoblasts depended on IRS-1 expression in osteoblasts and could not be rescued by IRS-1 expression in hemopoietic cells in the presence of not only IGF-I but also 1,25(OH)(2)D-3. In addition, osteoclast differentiation factor (RANKL/ODF) was not induced by these factors in IRS-1(-/-) osteoblasts. We conclude that IRS-1 deficiency in osteoblasts impairs osteoblast proliferation, differentiation, and support of osteoclastogenesis, resulting in low-turnover osteopenia. Osteoblastic IRS-1 is essential for maintaining bone turnover, because it mediates signaling by IGF-I and insulin and, we propose, also by other factors, such as 1,25(OH)(2)D-3.