title: GPR98/Gpr98 gene is involved in the regulation of human and mouse bone mineral density.
abstract: BACKGROUND
  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).
  
  
  METHODS
  We performed a search for 57,244 single-nucleotide polymorphisms (SNP) associated with BMD using SNP arrays and a replication study.
  
  
  METHODS
  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.
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bumkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Urano
authors.forename: Masataka
authors.initials: M
authors.lastname: Shiraki
authors.forename: Hideshi
authors.initials: H
authors.lastname: Yagi
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Noriko
authors.initials: N
authors.lastname: Sasaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Sato
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ouchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
mesh_terms: D000368:Aged; D000818:Animals; D015519:Bone Density; D002478:Cells, Cultured; D002678:Chimera; D005260:Female; D005269:Femur / Q000737:chemistry; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D055595:Mechanical Phenomena; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053245:RANK Ligand; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C417525:ADGRV1 protein, human; C485949:Adgrv1 protein, mouse; C505689:Tnfsf11 protein, mouse