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J. Biol. Chem., Vol. 280, Issue 32, 29011-29016, August 12, 2005

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A Novel Pathophysiological Mechanism for Osteoporosis Suggested by an in Vivo Gene Expression Study of Circulating Monocytes^*

Yao-Zhong Liu¶, Volodymyr Dvornyk¶||, Yan Lu, Hui Shen, Joan M. Lappe, Robert R. Recker, and Hong-Wen Deng**

From the Osteoporosis Research Center, Creighton University Medical Center and the Department of Biomedical Sciences, Creighton University, Omaha, Nebraska 68131, ^**The Key Laboratory of Biomedical Information and Engineering, Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China, the Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China, and the ^||Department of Biological Sciences, Kent State University, Kent, Ohio 44242

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® 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.

Received for publication, February 1, 2005 , and in revised form, May 3, 2005.

^* This work was supported by grants from National Institutes of Health (Grants K01 AR02170-01, R01 AR45349-01, and R01 GM60402-01A1) and an LB595 grant from the State of Nebraska. The study also benefited from grants from National Science Foundation of China, Huo Ying Dong Education Foundation, HuNan Normal University, Xi'an Jiaotong University, and the Ministry of Education of China. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental exclusion criteria and a supplemental table.

^¶ Both authors contributed equally to the work.

To whom correspondence should be addressed: Osteoporosis Research Center, Creighton University Medical Center, 601 N. 30th St., Ste. 6787, Omaha, NE 68131. Tel: 402-280-5911; Fax: 402-280-5034; E-mail: deng{at}creighton.edu.

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