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Human Molecular Genetics Advance Access originally published online on December 8, 2008
Human Molecular Genetics 2009 18(4):679-687; doi:10.1093/hmg/ddn397
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Pre-B-cell leukemia homeobox 1 (PBX1) shows functional and possible genetic association with bone mineral density variation

Ching-Lung Cheung1, Benjamin Y.Y. Chan1, Vivian Chan1, Shiro Ikegawa5, Ikuyo Kou5, Heidi Ngai1, David Smith2, Keith D.K. Luk3, Qing-Yang Huang1, Seijiro Mori6, Pak-Chung Sham4 and Annie W.C. Kung1,*

1 Department of Medicine 2 Department of Biochemistry 3 Department of Orthopaedics and Traumatology 4 Genome Research Centre, The University of Hong Kong, Pokfulam, Hong Kong, Republic of China 5 Laboratory for Bone and Joint Disease, Center for Genomic Medicine, RIKEN, Tokyo, Japan 6 Department of Internal Medicine, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

* To whom correspondence should be addressed at: Department of Medicine, The University of Hong Kong Pokfulam, Hong Kong, Republic of China. Tel: +86 85228554769; Fax: +86 85228162187; Email: awckung{at}hkucc.hku.hk

Received August 13, 2008; Accepted November 19, 2008

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.


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