Liu Yao-Zhong, Dvornyk Volodymyr, Lu Yan, Shen Hui, Lappe Joan M, Recker Robert R, Deng Hong-Wen
Osteoporosis Research Center, Creighton University Medical Center,Creighton University, Omaha, NE 68131, USA.
J Biol Chem. 2005 Aug 12;280(32):29011-6. doi: 10.1074/jbc.M501164200. Epub 2005 Jun 17.
Bone mineral density (BMD) is a major risk factor for osteoporosis. Circulating monocytes may serve as early progenitors of osteoclasts and produce a wide variety of factors important to bone metabolism. However, little is known about the roles of circulating monocytes in relation to the pathophysiology of osteoporosis. Using the Affymetrix HG-U133A GeneChip(R) array, we performed a comparative gene expression study of circulating monocytes in subjects with high and low BMD. We identified in total 66 differentially expressed genes including some novel as well as some already known to be relevant to bone metabolism. Three genes potentially contributing to bone metabolism, CCR3 (chemokine receptor 3), HDC (histidine decarboxylase, i.e. the histamine synthesis enzyme), and GCR (glucocorticoid receptor), were confirmed by quantitative real-time reverse transcriptase-PCR as up-regulated in subjects with lower BMD. In addition, significant negative correlation was observed between expression levels of the genes and BMD Z-scores. These three genes and/or their products mediate monocyte chemotaxis, histamine production, and/or sensitivity to glucocorticoids. Our results suggest a novel pathophysiological mechanism for osteoporosis that is characterized by increased recruitment of circulating monocyte into bone, enhanced monocyte differentiation into osteoclasts, as well as osteoclast stimulation via monocyte functional changes. This is the first in vivo microarray study of osteoporosis in humans. The results may contribute to identification of new genes and their functions for osteoporosis and suggest genetic markers to discern individuals at higher risk to osteoporosis with an aim for preventive intervention and treatment.
骨矿物质密度（BMD）是骨质疏松症的主要危险因素。循环单核细胞可能作为破骨细胞的早期祖细胞，并产生多种对骨代谢重要的因子。然而，关于循环单核细胞在骨质疏松症病理生理学中的作用知之甚少。我们使用Affymetrix HG-U133A基因芯片阵列，对高BMD和低BMD受试者的循环单核细胞进行了比较基因表达研究。我们总共鉴定出66个差异表达基因，包括一些新基因以及一些已知与骨代谢相关的基因。通过定量实时逆转录聚合酶链反应证实，三个可能对骨代谢有贡献的基因，即CCR3（趋化因子受体3）、HDC（组氨酸脱羧酶，即组胺合成酶）和GCR（糖皮质激素受体），在低BMD受试者中上调。此外，观察到这些基因的表达水平与BMD Z评分之间存在显著负相关。这三个基因和/或其产物介导单核细胞趋化、组胺产生和/或对糖皮质激素的敏感性。我们的结果提示了一种新的骨质疏松症病理生理机制，其特征是循环单核细胞向骨内的募集增加、单核细胞向破骨细胞的分化增强，以及通过单核细胞功能改变对破骨细胞的刺激。这是首次在人体中进行的骨质疏松症体内芯片研究。这些结果可能有助于识别骨质疏松症的新基因及其功能，并提示遗传标志物以辨别骨质疏松症高危个体，旨在进行预防性干预和治疗。
