Pre-B-cell leukemia homeobox 1 (PBX1) shows functional and possible genetic association with bone mineral density variation.
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.
Cheung
Ching-Lung
CL
Department of Medicine, The University of Hong Kong, Hong Kong, Republic of China.
Chan
Benjamin Y Y
BY
Chan
Vivian
V
Ikegawa
Shiro
S
Kou
Ikuyo
I
Ngai
Heidi
H
Smith
David
D
Luk
Keith D K
KD
Huang
Qing-Yang
QY
Mori
Seijiro
S
Sham
Pak-Chung
PC
Kung
Annie W C
AW
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*
D004268:DNA-Binding Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; C083400:PBX1 protein, human