Abstract
The distal end of mouse chromosome 1 (Chr 1) harbors quantitative trait loci (QTLs) that regulate bone mineral density (BMD) and share conserved synteny with human chromosome 1q. The objective of this article was to map this mouse distal Chr 1 region and identify gene(s) responsible for BMD regulation in females. We used X-ray densitometry [ie, dual-energy X-ray Absorptiometry (DXA), micro–computed tomography (µCT), and peripheral quantitative computed tomography (pQCT)] to phenotype a set of nested congenic strains constructed from C57BL/6BmJ (B6/Bm) and C3H/HeJ (C3H) mice to map the region associated with the BMD QTL. The critical region has been reduced to an interval of 0.152 Mb that contributes to increased BMD when C3H alleles are present. Histomorphometry and osteoblast cultures indicated that increased osteoblast activity was associated with increased BMD in mouse strains with C3H alleles in this critical region. This region contains two genes, Aim2, which binds with cytoplasmic dsDNA and results in apoptosis, and AC084073.22, a predicted gene of unknown function. Ovariectomy induced bone loss in the B6/Bm progenitor and the three congenic strains regardless of the alleles present in the critical BMD region. High dietary fat treatment (thought to suppress distal Chr 1 QTL for BMD in mice) did not induce bone loss in the congenics carrying C3H alleles in the critical 0.152 Mb carrying the AIM2 and AC084073.22 genes. Gene expression studies in whole bone of key congenics showed differential expression of AC084073.22 for strains carrying B6/Bm versus C3H alleles but not for Aim2. In conclusion, our data suggest that osteoblasts are the cellular target of gene action and that AC084073.22 is the best candidate for female BMD regulation in the distal region of mouse Chr 1. © 2011 American Society for Bone and Mineral Research.
Highlights
There is general recognition that skeletal traits are both environmentally and genetically complex
We and others have reported that the distal region of mouse chromosome 1 (Chr 1), which shares conserved synteny with the long arm (q) of human Chr 1, carries QTLs that regulate bone mineral density (BMD).[14,15] To capitalize on the control of experimental variables and the ease of gene mapping in mice, we developed a set of nested congenic strains that have allowed us to test which regions on Chr 1 are responsible for regulation of BMD.[16]. Using these nested congenic strains, we found that the BMD5 QTL on Chr 1 consists of three regions with sex- and site-specific bone-compartment effects.[14]. Here we present fine mapping of one of these regions designated QTL1
The congenic strains that demonstrate increased volumetric BMD (vBMD) all have C3H alleles for the shared critical 0.152 Mb critical region located between markers kls5-1 and rs6197487, whereas the 1-12-2 congenic, which does not have increased femoral vBMD, has B6/Bm alleles in this critical region (Fig. 2)
Summary
There is general recognition that skeletal traits are both environmentally and genetically complex. Enhancing that search has been remarkable growth in knowledge of bone biology over the past two decades and remarkable advancements in techniques and analytical methods within the genetics field. Investigations aimed at finding osteoporosis-related genes have adopted the genome-wide association approach using populations that have been phenotyped for bone mineral density (BMD) and densely genotyped. A number of reports have shown that regions and specific genes on human chromosome 1 (Chr 1) are associated with BMD, a widely used marker of osteoporosis. Ioannidis and colleagues have reported a meta-analysis of nine genome-wide association studies limited to women that found several chromosomal regions, including 1p13.3–1q23.3, with significant BMD association.[7] In two additional studies, Schaffer and colleagues[8] found significant association of BMD with 1q23 in young 25- to 45-year-old
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