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QTL mapping identifies a gene linked to bone mineral density
DOI:10.1038/bonekey.2012.142
Mukherjee et al. used quantitative trait locus (QTL) mapping to identify 11 loci in mice that are associated with femoral bone mineral density (BMD). Congenic mouse strains were then generated by crossing C57BL/6 and DBA/2 mice to analyze one particular gene located on chromosome 7. This revealed an allele in chromosome 7 of the DBA/2 mice that was associated with an increase in femoral BMD.
This high BMD trait was evident in mice of both sexes. Evaluation of osteoblasts obtained from the congenic mouse strain revealed that the high BMD trait was due to enhanced osteogenic differentiation of osteoblast precursors derived from the bone marrow of the long bones but not from neonatal tissues.
Further studies identified the most likely candidate gene on chromosome 7 as Ltbp4, one of a family of four murine genes that code for TGF-β, an important growth factor present in long bones. TGF-β is expressed by differentiating osteoblasts derived from mesenchymal stem cells; decreased expression of TGF-β in mice is associated with increased femoral BMD.
Editor's comment: Very few BMD genes have been definitively characterized to date. Here, QTL mapping identified a polymorphism in Ltbp4, a mouse gene that codes for one of the four proteins that controls bioavailability of TGF-β. The related genes LTBP2 and LTBP3 have been associated with BMD variation in human hips and with fracture; the role of human LTBP4 and its influence on human BMD therefore requires further investigation.
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