Context: Genetic factors are important in the development of osteoporosis.
Objective: The aim of this study was to search for novel genes that regulate bone mineral density (BMD).
Design: We performed a search for 57,244 single-nucleotide polymorphisms (SNP) associated with BMD using SNP arrays and a replication study.
Setting and patients: Baseline examinations were conducted in Japanese postmenopausal women. The mean (sd) age of the subjects was 66.5 (8.4) yr. We chose five SNP associated with BMD as those having lower combined P values between the first-stage (n = 251) and the second-stage (n = 499) analyses than the value determined by Bonferroni's correction. We also analyzed the bone-related phenotypes in knockout mice of a candidate gene.
Results: We focused on an SNP of G protein-coupled receptor 98 (GPR98) gene that showed a significant P value after the multiple-comparison tests in Japanese postmenopausal women. The subjects with one or two risk SNP (GG and AG genotype groups) had an increased risk of fractures (AA vs. GG + AG; P = 0.043). Femoral BMD was significantly lower in 12-wk-old Gpr98-knockout mice than in wild-type mice. A three-point bending test revealed that this morphological phenotype did in fact correlate with mechanical fragility in Gpr98-knockout mice. Compared with primary wild-type osteoblasts, primary Gpr98-deficient osteoblasts had increased Rankl expression and induced activity for osteoclastogenesis and osteoclastic function.
Conclusions: Genetic analyses in both human and mouse models uncovered the importance of the GPR98 gene in the regulation of bone metabolism.