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

Abstract

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.

Gene Expression Profiling in Bone Tissue of Osteoporotic Mice

“…Among genes involved in immune response we observed upregulation of chemokine receptor 2 (Ccr2). It has been suggested that upregulation of another chemokine receptor, CCR3 in circulating monocytes of individuals with low BMD may facilitate both the access of monocytes to the bone microenvironment and their subsequent differentiation into osteoclasts (6). Since it was shown that chemokine receptors CCR2b and CCR4 were potently induced by RANKL (22), we suggest that increased expression of Ccr2 was rather a consequence of elevated RANKL production due to increased bone remodeling, than a direct cause of increased bone resorption.…”

“…Furthermore, three genes with putative role in bone metabolism, namely CCR3 (chemokine receptor 3), HDC (histidine decarboxylase, i.e. the histamine synthesis enzyme), and GCR (glucocorticoid receptor) were upregulated in circulating monocytes of subjects with low BMD (6). In addition, increased production of IL-1 and tumour necrosis factor α (TNF-α) has been observed in circulating mononuclear cells in women with postmenopausal osteoporosis (7,8).…”

Response of the adipose tissue transcriptome to dihydrotestosterone in mice

“…We suggest, however, that the use of multiple time points and a rather stringent filtering procedure decreased the likelihood of identified false positives. Our results nevertheless suggest that careful validation on a different platform remains an absolute necessity (27).…”

Molecular disease map of bone characterizing the postmenopausal osteoporosis phenotype

“…It was cautioned that the analyses had limited power and that effect sizes were very modest, reinforcing the belief that there are many more sequence variants relevant to osteoporosis to be identified. (13,29) Liu and colleagues (31) used microarray technology to study gene expression in circulating blood monocytes from women with high or low BMD. While circulating blood cells are easily obtainable and represent an attractive source of biologic material for diagnostic purposes, they do not reflect local processes in bone, the primary site of osteoporosis.…”