Gene expression profile induced by ovariectomy in bone marrow of mice: A functional approach to identify new candidate genes associated to osteoporosis risk in women

Osteoporosis is a multifactorial skeletal pathology with a main genetic component. To date, however, the majority of genes associated with this pathology remain unknown since genes cataloged to date only explain a part of the heritability of bone phenotypes. In the present study, we have used a genome-wide gene expression approach by means of microarrays to identify new candidate genes involved in the physiopathology of osteoporosis, using as a model the ovariectomized (OVX) mice by comparing global bone marrow gene expression of the OVX mice with those of SHAM operated mice. One hundred and eighty transcripts were found to be differentially expressed between groups. The analysis showed 23 significant regulatory networks, of which the top five canonical pathways included B-cell development, primary immunodeficiency signaling, PI3K signaling in B-cells, phospholipase C signaling, and FcgRIIB signaling in B-cells. Twelve differentially expressed genes were validated by MALDI-TOF mass spectrometry with good reproducibility. Finally, the association to bone phenotypes of SNPs in genes whose expression was increased (IL7R and CD79A) or decreased (GPX3 and IRAK3) by OVX in mice was analyzed in a cohort of 706 postmenopausal women. We detected an association of a SNP in a gene involved in the detoxification of free radicals like glutathione peroxidase 3 (GPX3) with femoral neck BMD (rs8177447, P = 0.043) and two SNPs in the Ig-alpha protein of the B-cell antigen component gene (CD79A) with lumbar spine BMD (rs3810153 and rs1428922, P = 0.016 and P = 0.001, respectively). These results reinforce the role of antioxidant pathways and of B-cells in bone metabolism. Furthermore, it shows that a genome-wide gene expression approach in animal models is a useful method for detecting genes associated to BMD and osteoporosis risk in humans.