Deficiency of insulin receptor substrate-1 impairs skeletal growth through early closure of epiphyseal cartilage
Deficiency of insulin receptor substrate-1 impairs skeletal growth through early closure of epiphyseal cartilage
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DOI：
10.1359/jbmr.0301221
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发表时间：
2004-02-01
影响因子：
6.2
通讯作者：
Kawaguchi, H
中科院分区：
文献类型：
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作者：
Hoshi, K;Ogata, N;Kawaguchi, H
前言：胰岛素样生长因子-1(IRS-1)是胰岛素样生长因子-I(IGF-I)和胰岛素的细胞内信号转导所必需的分子，两者都是软骨和骨代谢的有效合成代谢调节剂。为了阐明IRS-1信号在骨骼生长中的作用，对IRS-1(-/-)基因缺陷小鼠(IRS-1(-/-))四肢和躯干比野生型(WT)小鼠的四肢和躯干短20-30%的骨骺软骨内和周围进行了形态分析。材料和方法：用组织学、免疫组织化学、酶细胞组织化学、超微结构和骨组织形态计量学方法比较了纯合子IRS-1(-/-)和WT雄性仔鼠的骨骺软骨和胫骨近端的初级海绵组织。IRS-1和胰岛素样生长因子(IGF)-I受体广泛表达，而IRS-2弱定位于骨细胞。年代学观察发现，WT小鼠增殖区高度和肥大软骨细胞大小随年龄增长而减小，IRS-1(-/-)软骨细胞增殖区高度和肥大软骨细胞体积减小的速度加快，12周时的表现与24周时相似。在IRS-1(-/-)软骨中，增殖细胞核抗原(PCNA)或甲状旁腺激素(PTH)/甲状旁腺激素相关肽(PTHrP)受体阳性的增殖软骨细胞在12周时几乎消失。相反，肥大带内TUNEL+凋亡细胞增多，肥大带底部大部分软骨细胞被钙化的基质包裹，提示软骨闭合。在原发海绵中，骨体积、碱性磷酸酶(ALP)(+)成骨细胞、TRACP(+)破骨细胞和骨桥蛋白阳性骨水泥线明显减少。IRS-1(-/-)小鼠骨形成和骨吸收的骨组织形态计量学参数均显著低于对照组，提示骨转换受到抑制。结论：IRS-1(-/-)骨赘软骨表现为软骨细胞增殖不足，肥大软骨细胞钙化，细胞凋亡加速，生长板早期关闭。因此，这些数据有力地表明，IRS-1信号对于骨骼的生长是重要的，因为它防止了骨骺软骨的早期关闭，并维持了随后在初级海绵体内的骨转换。
Introduction: IRS-1 is an essential molecule for intracellular signaling by IGF-I and insulin, both of which are potent anabolic regulators of cartilage and bone metabolism. To clarify the role of IRS-1 signaling in the skeletal growth, morphological analyses were performed in and around the epiphyseal cartilage of mice deficient in IRS-1 (IRS-1(-/-)), whose limbs and trunk were 20-30% shorter than wildtype (WT) mice.Materials and Methods: The epiphyseal cartilage and the primary spongiosa at proximal tibias of homozygous IRS-1(-/-) and WT male littermates were compared using histological, immunohistochemical, enzyme cytohistochemical, ultrastructural, and bone histomorphometrical analyses.Results: In and around the WT epiphyseal cartilage, IRS-1 and insulin-like growth factor (IGF)-I receptors were widely expressed, whereas IRS-2 was weakly localized in bone cells. Chronological observation revealed that height of the proliferative zone and the size of hypertrophic chondrocytes were decreased in WT mice as a function of age, and these decreases were accelerated in the IRS-1(-/-) cartilage, whose findings at 12 weeks were similar to those of WT at 24 weeks. In the IRS-1(-/-) cartilage, proliferating chondrocytes with positive proliferating cell nuclear antigen (PCNA) or parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor immunostaining had almost disappeared by 12 weeks. Contrarily, TUNEL+ apoptotic cells were increased in the hypertrophic zone, at the bottom of which most of the chondrocytes were surrounded by the calcified matrix suggesting the closure of the cartilage. In the primary spongiosa, bone volume, alkaline phosphatase (ALP)(+) osteoblasts, TRACP(+) osteoclasts, and the osteopontin-positive cement line were markedly decreased. Bone histomorphometrical parameters for both bone formation and resorption were significantly lower in IRS-/- mice, indicating the suppression of bone turnover.Conclusion: The IRS-1(-/-) epiphyseal cartilage exhibited insufficient proliferation of chondrocytes, calcification of hypertrophic chondrocytes, acceleration of apoptosis, and early closure of the growth plate. Thus, the data strongly suggest that IRS-1 signaling is important for the skeletal growth by preventing early closure of the epiphyseal cartilage and by maintaining the subsequent bone turnover at the primary spongiosa.