title: Pre-B-cell leukemia homeobox 1 (PBX1) shows functional and possible genetic association with bone mineral density variation.
abstract: Bone mineral density (BMD) is one of the major determinants of risk for osteoporotic fracture. Multiple studies reveal that peak bone mass is under strong genetic influence. One of the major susceptibility loci for peak spine BMD has been mapped to chromosome 1q21-q23 in the Caucasian population. We have previously replicated this finding in Southern Chinese pedigrees and detected a maximum multipoint log of odds (LOD) score of 2.36 in this region. To further fine-map this region, 380 single-nucleotide polymorphic (SNP) markers were genotyped in 610 sibpairs from 231 families. Several markers were identified in the association analysis as important candidates underlying BMD variation. Among them, successful replication was demonstrated for SNPs in pre-B-cell leukemia homeobox 1 (PBX1) gene in two other unrelated case-control cohorts. The functional role of PBX1 in bone metabolism was examined in vitro using human bone-derived cells (HBDC) and murine MC3T3-E1 pre-osteoblasts. PBX1 mRNA was constitutively expressed in both HBDC and MC3T3-E1 cells. Immunostaining revealed that PBX1 is localized in the nucleus compartment. Silencing of PBX1 by RNAi in MC3T3-E1 cells decreased the expression of Runx2 and Osterix, the critical transcription factors for osteogenesis, but accelerated cell proliferation and bone nodule formation. Overall, our data suggest a genetic and functional association of PBX1 with BMD.
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, Republic of China.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Cheung
authors.forename: Benjamin Y Y
authors.initials: BY
authors.lastname: Chan
authors.forename: Vivian
authors.initials: V
authors.lastname: Chan
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Kou
authors.forename: Heidi
authors.initials: H
authors.lastname: Ngai
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: Keith D K
authors.initials: KD
authors.lastname: Luk
authors.forename: Qing-Yang
authors.initials: QY
authors.lastname: Huang
authors.forename: Seijiro
authors.initials: S
authors.lastname: Mori
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Annie W C
authors.initials: AW
authors.lastname: Kung
mesh_terms: D000818:Animals; D044466:Asian People / Q000235:genetics; D015519:Bone Density; D016022:Case-Control Studies; D002460:Cell Line; D002681:China; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; C083400:PBX1 protein, human