Correlation of insulin-like growth factor-1 and bone metabolism-related indexes in postmenopausal osteoporosis

doi:10.3969/j.issn.2095-4344.2017.36.021

Abstract

Abstract:

BACKGROUND: Increasing evidence has shown that insulin-like growth factor-1 (IGF-1) plays a regulatory role in bone metabolism and increases bone formation, stimulates osteoblast number and activity, as well as reduces osteoclast differentiation and bone resorption. The mechanism of IGF-1 is an issue of concern.
OBJECTIVE: To review the research advance in IGF-1 and the bone metabolism-related indexes in postmenopausal osteoporosis.
METHODS: The first author searched the PubMed and CNKI databases between January 2012 and July 2016 using the keywords of “postmenopausal osteoporosis, insulin-like growth factor, bone metabolism, biochemical markers” in English and Chinese, respectively. The repetitive articles were excluded, and 36 eligible articles were enrolled for overview.
RESULTS AND CONCLUSION: Bone resorption is increased in postmenopausal woman through the regulation of a variety of cytokines, in which IGF-1 in the blood is combined with IGF binding protein 3, making growth hormone play its biological role. In addition, the growth hormone in the blood directly acts on the adipose tissue, and muscle and bones. Growth hormone exerts a direct effect on bone tissue, promotes osteoblast maturation and differentiation, and enhances the expression of collagen and non-collagen through IGF-1-mediated indirect effect, thus promoting bone formation. The process of bone metabolism is able to reflect the activities of osteoblasts and osteoclasts and the changes of bone matrix and bone mineralization. In vitro experiments show that IGF-1 stimulates the proliferation of osteoblast precursors and differentiate into osteoblasts in a dose-dependent manner, promotes the expression of osteogenic markers such as alkaline phosphatase, type I collagen, and osteocalcin, and also stimulates the activity and number of osteoclasts. However, there are few clinical reports and few observation indicators, resulting in a lack of reference range for the detection and treatment of osteoporosis, which needs further exploration.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Osteoporosis, Postmenopausal, Insulin-Like Growth Factor I, Growth Hormone, Tissue Engineering

CLC Number:

R318

Dong Mei, Wu Jian, Han Xing-mei, Jin Shu-xia. Correlation of insulin-like growth factor-1 and bone metabolism-related indexes in postmenopausal osteoporosis[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(36): 5862-5867.

Figures/Tables 2

2.1 胰岛素样生长因子1与绝经后骨质疏松症绝经后骨质疏松症，即绝经后妇女由于雌激素水平急剧下降，破坏了对骨局部因子、生长因子以及体液因子的调控，导致骨量减少及骨组织结构变化，刺激骨转换加快，骨吸收的抑制减弱，使骨脆性增多易于骨折，造成骨质丢失[4]。女性的骨量是在骨骼的生长发育青春期完成或20岁左右增加达到峰值骨量。然后，持续稳定状态一段时间，40岁之后男性与女性的骨量随着年龄逐渐的降低，但其下降幅度随个人、种族以及性别不同。特别是，女性与雌性激素的减少与松质骨快速骨丢失主要是由于卵巢功能衰退(绝经后骨量减少，绝经骨质疏松症)，之后逐渐缓慢降低。雌激素对骨代谢产生重要的影响，雌激素作用于成骨细胞和破骨细胞，使得骨吸收和骨形成同时保持稳态平衡状态从而维持骨量。雌激素对于骨骼或者其他器官均由核内受体介导表达，成骨细胞，破骨细胞以及骨细胞均具有雌激素受体样作用。对于成骨细胞，胰岛素样生长因子1可抑制细胞凋亡，刺激细胞增殖。由于这些生长因子对于骨和软骨具有同化作用，因此考虑它们可通过自分泌作用介导增加骨量。另外对于成骨细胞刺激RANKL的诱饵受体即破骨细胞分化抑制因子，从而抑制RANKL/RANK系统，抑制破骨细胞的前体细胞向破骨细胞分化。胰岛素样生长因子1是人体在生长激素刺激下产生的激素，是多种激素与细胞因子调节骨代谢复杂网络的核心因素。当脑垂体前叶分泌生长激素，在数分钟内，可促进肝细胞合成分泌胰岛素样生长因子1。胰岛素样生长因子1被细胞分泌后会与邻近细胞表面含有胰岛素样生长因子1的受体结合，它具有酪氨酸激酶活性，引起细胞内反应，促进细胞生长。研究证实，雌二醇可通过雌激素受体提高成熟成骨细胞和成骨细胞前体的胰岛素样生长因子1 mRNA水平，并呈时间和剂量依赖性[5-6]。张金山等[7]观察绝经后1-3年妇女骨密度与胰岛素样生长因子1的变化与关系，发现胰岛素样生长因子1降低可能是影响绝经后早期骨密度降低的主要危险因素。易伟莲等[8]发现绝经后骨质疏松患者胰岛素样生长因子1水平明显下降，而且胰岛素样生长因子1与骨密度、雌二醇呈显著正相关，与年龄呈显著负相关。因此，可以考虑胰岛素样生长因子1基因为雌激素发挥抗骨质疏松作用的一个重要靶基因。 2.2 胰岛素样生长因子1与骨代谢指标骨代谢标志物迅速发展，在骨质疏松症等代谢性骨病的诊断，疗效评估和检测病情中应用日趋广泛，骨代谢的过程往往能反映成骨细胞和破骨细胞的活动及骨基质和骨矿化的变化[9-10]。体外实验中，胰岛素样生长因子1不仅可呈剂量依赖性刺激成骨细胞前体的增殖并向成骨细胞进行分化、促进碱性磷酸酶、Ⅰ型胶原以及骨钙素等成骨标志物的表达，并且还可刺激破骨细胞的活性和数目的增加(图1及表1)。 2.2.1 胰岛素样生长因子1与骨形成指标骨特异性碱性磷酸酶：是评价骨形成和骨转换的指标，基因定位于1号染色体。骨特异性碱性磷酸酶由成骨细胞分泌，在骨形成及矿化过程中起重要作用[9]。在成骨过程中它可水解磷酸酯，为羟磷灰石的沉积提供必需的磷酸，同时水解焦磷酸盐，解除其对骨矿盐形成的抑制作用，从而有利于成骨过程。因此，骨特异性碱性磷酸酶是成骨细胞成熟和具有活性的标志物，它被认为是最精确的骨形成标志物。郭玲等[11]在体外培养的小鼠成骨细胞中分别加入 25，50，100及200 μg/L 的胰岛素样生长因子1，结果发现胰岛素样生长因子1在此浓度范围内能显著提高成骨细胞内的碱性磷酸酶活性，并呈明显的剂量依赖效应。骨钙素：是成骨细胞产生的骨特异性蛋白，是由依赖维生素K的γ-羧化谷氨酸蛋白即49个氨基酸组成的多肽。骨钙素是骨钙素基因转录和表达的产物，它主要参与维持骨骼正常矿化速率，并在骨骼生长以及羟磷灰石沉积时增加，是骨形成和骨转换的标志物之一[12]。胰岛素样生长因子1干预共同培养的成骨细胞和破骨细胞12 h后，明显促进成骨细胞骨钙素基因的表达并增加培养基中骨钙素蛋白含量[13]。Zhang等[14]的研究发现胰岛素联合胰岛素样生长因子1也能显著诱导基因小鼠的骨钙素启动子的活动。 Ⅰ型前胶原羧基端前肽和Ⅰ型前胶原氨基端肽：成骨细胞首先合成原胶原，在原胶原的N-端和C-端各自有一个延长肽，即Ⅰ型前胶原羧基端前肽和Ⅰ型前胶原氨基端肽蛋白酶将两端的肽切断后形成成熟的胶原。Ⅰ "

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