Research advances in adiponectin preventing osteoporosis by bone metabolism regulation

doi:10.3969/j.issn.2095-4344.0212

Abstract

Abstract:

BACKGROUND: Adiponectin is one of the adipocytokines that have been found to be negatively correlated with obesity in recent years. As an endogenous bioactive peptide, adiponectin is shown to be associated with insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and participate in the regulation of bone metabolism.
OBJECTIVE: To describe the mechanism of adiponectin in bone metabolism, and mainly clarify the correlation of adiponectin with osteoblasts and osteoclasts.
METHODS: The first author searched PubMed and CNKI databases for the articles addressing the experimental research and research progress of adiponectin in bone metabolism published from 2003 to 2017. The keywords were “adiponectin, osteoporosis, bone metabolism, osteogensis, bone absorption” in English and Chinese, respectively. Adiponectin, its receptors, bone metabolism, adiponectin effects on bone formation and bone resorption were reviewed.
RESULTS AND CONCLUSION: Adiponectin exerts a comprehensive effect on bone metabolism, mainly through autocrine, paracrine and endocrine, insulin signaling pathways. Besides, it exerts biological effects mostly by regulating OPG/RANKL/RANK system, especially in bone formation and bone resorption. Therefore, adiponectin may prevent osteoporosis by regulating bone metabolism.

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: Tissue Engineering, Adiponectin, Osteogensis

CLC Number:

R318

Huang Lei-tao1, Wu Xia2, Lai Qi1, Chen Gui-ping1, Liu Yuan1, Zhang Bin1, Dai Min1. Research advances in adiponectin preventing osteoporosis by bone metabolism regulation[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(12): 1944-1949.

Figures/Tables 1

2.1 脂联素及其受体概述脂联素(adiponectin，APN)又名 Acrp30，adipoQ，ApM1，是目前为止发现的与肥胖呈负相关的脂肪细胞因子之一。在动脉粥样硬化中，脂联素被认为是一种保护因子，而在一些自身免疫性疾病如类风湿性及风湿性关节炎中，则被认为具有前炎性因子的作用[8]。脂联素主要是由成熟的脂肪细胞合成和分泌，具有一定的多功能激素蛋白[9]。人脂联素分子全长包含244个氨基酸，一级序列结构包括4个结构域[10]：氨基末端的信号序列、一小段非螺旋区、一段22个氨基酸组成的胶原重复序列以及羧基末端球形功能区[11]。基因位于3q27，片段长约17 kb，包含3个外显子和2个内含子组成[12]。脂联素是血浆中最丰富的特异性脂肪细胞因子，其表达量一般是常见激素的3倍，而且在女性中偏高，但研究证实其与昼夜节律及年龄变化无明显关系[13]。血清中脂联素的质量浓度为5-30 μg/L，占总血清蛋白的0.01%以上，脂联素是一个在肥胖患者体内水平下调的脂肪因子[14]。脂联素以不同形式存在，其存在形式主要因胶原结构域的不同而被区分，形成低、中、高相对分子质量的3种主要聚合物形式[15-17]，其中脂联素在体内循环中主要以高分子量形式存在[18-19]。体内脂联素水平受多种因素的影响，研究表明女性血浆中脂联素的水平明显高于男性，且在进入青春期后更加显著，这可能与男性雄激素对脂联素分泌有抑制作用有关[20]。脂联素存在2种受体，最早是由Yamauchi等[21]在2003年提出来的，他们在用Northern Blot测定法克隆出脂联素受体基因的cDNA全长时，发现其存在两种异构体，后来命名为脂联素受体1，2，其中脂联素受体1分布广泛，主要存在于骨骼肌中；而脂联素受体2 在肝脏中分布最多[22]。脂联素的生物学效应主要是通过脂联素受体1，2来介导的，主要通过激活腺苷酸激酶、促分裂素原活化蛋白激酶和过氧化物酶体增生物激活受体α 配体，最终来促进骨骼肌细胞的脂肪酸氧化和糖吸收，降低体内血脂浓度及葡萄糖水平，是人体的脂质代谢和血糖稳态的调控网络中的重要调节因子[23]。不同受体与不同形式的根据脂联素受体的类型与其结合的亲和力也有所不同，脂联素受体1，2与脂联素单体亲和性较高，不同型式脂联素的生物学作用可能有较大差别[24-25]。许多研究表明，脂联素与胰岛素抵抗、动脉粥样硬化及抗炎作用密切相关[26-30]。在体外动物模型中，脂联素具有改善肥胖相关性疾病的作用，如由肥胖引起人体内胰岛素抵抗、葡萄糖耐量异常、2 型糖尿病等[31-32]。 2.2 骨组织的生理代谢骨组织代谢是通过成骨细胞和破骨细胞参与的骨形成与骨吸收来实现的，其代谢活动是一个动态平衡过程[1，33]。在人的生长期，骨形成大于骨吸收，骨量呈线性增长，表现为骨皮质增厚，骨松质更密集，这一过程称为骨构建或骨塑形。在成人期，骨生长停止，但骨的形成和吸收仍在继续，处于一种平衡状态，称为骨重建。骨重建开始于骨吸收，随后是骨形成。骨的吸收与形成连续进行，最终使骨能不断地自我修复和适应新的应力要求[11]。正常成熟骨的代谢主要以骨重建方式进行，在骨代谢调节激素和局部细胞因子的协调作用下，骨组织通过体内骨形成与骨吸收之间相互影响及制约，使体内骨转换达到一个动态的平衡状态，以维持人体正常骨的生理代谢效应[34]。骨组织在整个生命活动过程中都具有新陈代谢的活性，骨基质、骨矿物质以及骨代谢生化标志物的变化来反映。其中骨密度是反映骨质疏松程度，预测骨折危险性的重要依据。骨密度是定量评估骨骼强度的一个重要指标，通常使用T值判断骨密度是否正常，它会随着成年后年龄的增长和体内雌激素水平的降低而逐年下降，尤其在女性中表现的更为明显[1]。 2.3 脂联素与成骨、破骨之间的关系查阅近年来国内外文献发现，脂联素对骨密度具有一定调控作用。通过绝经前后的女性体内脂联素和骨密度检测发现两者之间呈现负相关性，同时与体内体脂含量和非脂肪含量存在负相关，认为脂联素是骨密度的独立预测因子。同样研究表明，脂联素影响骨的代谢，可通过3个不同的途径[1，35]：①自分泌或旁分泌的途径；②内分泌途径；③通过影响胰岛素信号通路产生作用。脂联素对骨代谢的作用既可以影响成骨细胞的活性，又可以影响破骨细胞的活性，是上述3个途径综合作用的结果[36](图1)。有学者研究发现，在破骨细胞诱导实验中，以不同浓度的脂联素作用细胞，脂联素对破骨细胞的作用呈浓度依赖关系[37]，并且其可能通过抑制破骨细胞中生成的关键转录因子——核转录因子κB来起作用的，提示脂联素可能影响破骨细胞的活性来调节骨代谢。有研究通过研究发现，脂联素和瘦素在体内的水平都能通过影响成骨及破骨的活性来调控骨代谢[13]，使人体的骨形成和骨吸收处"

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