Ghrelin participates in bone metabolism: the newest research progress

doi:10.3969/j.issn.2095-4344.2017.12.023

Abstract

Abstract:

BACKGROUND: Ghrelin is a newly discovered brain-gut peptide from the stomach of human and rats. As an endogenous ligand for growth hormone secretagogue receptor (GHSR), ghrelin can notably stimulate the release of growth hormone. Although GHSR is expressed in many peripheral tissues, little is known about the influence of ghrelin on bone metabolism and GHSR expression in bone tissue.
OBJECTIVE: To review the research progress of ghrelin in bone metabolism.
METHODS: The first author retrieved CNKI, WanFang, PubMed, and Springerlink databases with the keywords of “Ghrelin, bone metabolism” in Chinese and English, respectively. The studies regarding ghrelin and its involvement in bone metabolism were included, and repetitive ones were excluded. A total of 53 eligible literatures were selected through skimming abstracts.
RESULTS AND CONCLUSION: Ghrelin is a peptide composed of 28 amino acids discovered in gastric endocrine cells and hypothalamic arcuate nucleus in mice and human, which makes a great effect on digestive, nervous, immune and endocrine systems, and also plays a role in hormone secretion, glucose metabolism, immunity, cell proliferation, and inflammation. Serum ghrelin makes a certain influence on bone growth and development, and promotes the differentiation and proliferation of osteoblasts, and inhibits its apoptosis. Additionally, ghrelin suppresses the early osteogenic differentiation of C3H10T1/2 cells by upregulating the expression of Runx2 protein, and attenuates adipogenic differentiation by downregulating PPARγ2 expression, thus inducing osteogenic differentiation. However, few studies have addressed the expression of GHSR in bone tissue.

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: Ghrelin, Bone and Bones, Tissue Engineering

CLC Number:

R318

Chen Hong1, Bi Ran-ran2, Chen Liang1, Zhu Qiong1. Ghrelin participates in bone metabolism: the newest research progress[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(12): 1940-1945.

Figures/Tables 1

2.1 Ghrelin的概况 1999年日本科学家Kojima等[1]利用免疫组织化学的方法在小鼠和人的胃内分泌细胞及下丘脑弓状核发现了一种含有28个氨基酸残基的多肽，它是生长激素促分泌素受体的内源性配体，Ghrelin 在体内的多个组织中均有表达，但是以胃黏膜内的表达量最高[2]。Ghrelin全肽的半衰期是 27-31 min，酰基化的Ghrelin半衰期是9-13 min[3]。 2.1.1 Ghrelin的合成与分布 Ghrelin由28个氨基酸残基组成，相对分子质量为3 314，它有2种形式：Ghrelin-25和Des-Gln14-Ghrelin[4]。Des-Glnl4-Ghrelin生物学活性与Ghrelin相同，第14位上是谷氨酞胺。大鼠和人类Ghrelin氨基酸序列具有较高的同源性，Ghrelin第3位丝氨酸残基被辛酰基化，该辛酰基结构是Ghrelin生物活性所必需的[1]。Date等[5]研究发现：胃肠道黏膜均有Ghrelin分泌细胞，即X/A样内分泌细胞，主要位于胃底黏膜泌酸腺的体部和底部，十二指肠、回肠、盲肠、结肠的分泌量很少；其释放Ghrelin的机制可能是胃肠道的Ghrelin细胞与固有层的毛细血管网紧密接触，接受胃肠道管腔的物理刺激和/或基底膜外侧的化学刺激，从而释放Ghrelin。Gnanapavan等[5-6]通过免疫组织化学和原位杂交研究发现：胃肠道黏膜均有Ghrelin mRNA的表达.Ghrelin的mRNA存在于胃底泌酸腺的颈部和底部[1]。也有人通过原位杂交和RT-PCR均证实Ghrelin mRNA在中枢神经系统也有表达，下丘脑弓状核、垂体、脑干等中枢神经系统亦有Ghrelin的分泌[1，7]，故称之为脑-肠肽。Gnanapavan等[6]研究发现：机体许多组织器官均有Ghrelin mRNA表达。这些发现说明Ghrelin分布较广泛。 2.1.2 Ghrelin的受体促生长激素分泌物受体研究表明Ghrelin通过与细胞表面相应的受体促生长激素分泌物受体结合发挥生物学作用。促生长激素分泌物受体属于α螺旋7次跨膜的G蛋白偶联受体[8]，主要G蛋白是Gq蛋白，主要的信号传递分子是磷脂酶C(phospholipase C，PLC)、三磷酸肌醇(inositol-triphosphate，IP3)和蛋白激酶C(protein kinase C，PKC)。促生长激素分泌物受体存在促生长激素分泌物受体1α和促生长激素分泌物受体1b两种亚型[4]。其中1α型由366个氨基酸组成，含7个跨膜结构域(transmembrane domains，TMD)，是受体功能的主要形式。研究表明，Ghrelin是与1α型促生长激素分泌物受体结合而发挥其生物学作用的[9]。Ghrelin与促生长激素分泌物受体1α结合后，主要激活磷脂酶C、三磷酸肌醇和蛋白激酶C、有丝分裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)等信号通路而发挥相应的效应。1b型由289个氨基酸组成，含5个跨膜结构域；1b不介导生物学效应。促生长激素分泌物受体1a在多种组织中均有表达，主要在垂体表达，同时在下丘脑弓状核、甲状腺、胰腺、脾、心肌、肾上腺也有低水平表达，促生长激素分泌物受体1b也在多种组织中有广泛表达[10] 2.2 Ghrelin的生理作用 2.2.1 对消化系统的影响 Ghrelin参与胃功能的中枢和外周调节。新近研究发现，脑室和室旁核注入Ghrelin可促进大鼠摄食，增加与摄食相关核团，如下丘脑室旁核、背内侧核、弓状核、延髓孤束核和最后区的c-Fos表达[11-12]。同时，Ghrelin可加速胃排空、增加胃酸分泌及促进结肠运动[13]。Ghrelin也可以促进小肠转运，其促动力作用由其受体促生长激素分泌物受体所介导；静脉给予Ghrelin可通过肠神经系统和中枢神经系统调节小肠运动[14](图2)。Ghrelin受体的激活可发挥多种生理学作用，可刺激胃酸分泌和胃排空、加快小肠蠕动、改善术后肠梗阻症状[15]。 2.2.2 对内分泌系统的影响 Ghrelin与血糖调节有关。李丽等[16]研究表明：糖尿病大鼠血浆Ghrelin水平显著升高。Ghrelin 可影响肝脏糖代谢及胰岛素水平，进而调节外周血糖稳态[17]。Gauna等[18]研究表明，非酰化"

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