Identification of mouse Duffy Antigen Receptor for Chemokines (Darc) as a BMD QTL gene

Abstract

It is now well known that bone mineral density (BMD) variance is determined by both genetic and environmental factors. Accordingly, studies in human and animal models have revealed evidence for the presence of several quantitative trait loci (QTL) that contribute to BMD variations. However, the identification of BMD QTL genes remains a big challenge. In the current study, we focused our efforts to identify the BMD candidate gene in chromosome 1 (Chr 1) QTL that was detected from a cross involving high BMD CAST/EiJ (CAST) and low BMD C57BL/6J (B6) mice. To this end, we have combined several approaches including: (1) fine mapping the BMD QTL in Chr 1 of the B6.CAST F 2 female mice using a large number of polymorphic markers; (2) the generation of congenic sublines of mice by repeated backcrossing of CAST with B6 mice and phenotype characterization; (3) expression profiling genes in the QTL region; and (4) SNP analyses to identify the mouse Duffy Antigen Receptor for Chemokines (Darc) as a candidate gene for Chr 1 BMD QTL2. We verified the involvement of the Darc protein in BMD variation by evaluating the skeletal phenotype of Darc-knockout mice and congenic sublines of mice carrying small chromosomal segments from CAST BMD QTL. Based on the findings that Darc-antibody blocked formation of multinucleated osteoclasts in vitro and that Darc from CAST binds chemokines, known to regulate osteoclast formation, with reduced affinity compared with Darc from B6 mice, we conclude that Darc regulates BMD negatively by increasing osteoclast formation, and that the genetic association between Darc gene polymorphism and BMD variations in humans merits investigation.[Supplemental material is available online at www.genome.org.]Osteoporosis is a condition associated with decreased bone strength and an increased fracture risk. Its prevalence is increasing as more individuals with low bone mineral density (BMD), the strongest predictor of fracture risk, are detected. Thus, molecular dissection of the BMD regulatory system may reveal novel therapeutic targets for the treatment of osteoporosis. Several studies preformed on both humans and mice have shown that BMD has a strong heritable component, with estimates that genes account for 60%-80% of BMD variance (Morrison et al.

Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators

“…33 Mice lacking only endothelial Darc exhibit deficient leukocyte emigration, 27 and recent studies have identified DARC as a major regulator of murine bone mineral density through a role in cytokine-mediated osteoclastogenesis. 34 Although in general recent GWA studies have reported small effect sizes, we found a single variant, DARC rs12075 (Asp42Gly), that explains approximately 20% of the variation in MCP-1 serum concentration, which is considerably greater than all previously known correlates combined. 13 It is notable that DARC is a trans-acting variant and is not on the same chromosome as the gene coding for MCP-1 (CCL2).…”

Haploinsufficiency of osterix in chondrocytes impairs skeletal growth in mice

“…It is now known that genetic variations influencing gene expression contribute to differences in peak bone mass in humans (6,14). In our mouse model, we found that haploid insufficiency of Osx in chondrocytes caused delayed skeletal growth reflected by reduced total body length and weight, as well as reduced BMC and BMD in long bones of young mice.…”

Gene Encoding Duffy Antigen/Receptor for Chemokines Is Associated with Asthma and IgE in Three Populations

“…CC and CXC chemokines are potent chemoattractants for eosinophils, basophils, monocytes, and T cell subsets and are believed to be crucial mediators of inflammation in asthma (40,41). DARC has previously been associated with the inflammatory process in prostate cancer (42,43), preeclampsia in women from West Africa (44), and bone mineral density in a murine model (45). Similar to asthma, these clinical conditions exhibit a different prevalence between African Americans and individuals of European descent (46,47), which may also be explained by variations in the exposure stimulating chemokines and/or differences in the function of DARC among these populations.…”