title: Congenic mice provide in vivo evidence for a genetic locus that modulates intrinsic transforming growth factor β1-mediated signaling and bone acquisition.
abstract: Osteoporosis, the most common skeletal disorder, is characterized by low bone mineral density (BMD) and an increased risk of fragility fractures. BMD is the best clinical predictor of future osteoporotic fracture risk, but is a complex trait controlled by multiple environmental and genetic determinants with individually modest effects. Quantitative trait locus (QTL) mapping is a powerful method for identifying chromosomal regions encompassing genes involved in shaping complex phenotypes, such as BMD. Here we have applied QTL analysis to male and female genetically-heterogeneous F(2) mice derived from a cross between C57BL/6 and DBA/2 strains, and have identified 11 loci contributing to femoral BMD. Further analysis of a QTL on mouse chromosome 7 following the generation of reciprocal congenic strains has allowed us to determine that the high BMD trait, which tracks with the DBA/2 chromosome and exerts equivalent effects on male and female mice, is manifested by enhanced osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro and by increased growth of metatarsal bones in short-term primary culture. An insertion/deletion DNA polymorphism in Ltbp4 exon 12 that causes the in-frame removal of 12 codons in the DBA/2-derived gene maps within 0.6 Mb of the marker most tightly linked to the QTL. LTBP4, one of four paralogous mouse proteins that modify the bioavailability of the transforming growth factor β (TGF-β) family of growth factors, is expressed in differentiating MSC-derived osteoblasts and in long bones, and reduced responsiveness to TGF-β1 is observed in MSCs of mice homozygous for the DBA/2 chromosome 7. Taken together, our results identify a potential genetic and biochemical relationship between decreased TGF-β1-mediated signaling and enhanced femoral BMD that may be regulated by a variant LTBP4 molecule.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Mukherjee
authors.forename: Emily A
authors.initials: EA
authors.lastname: Larson
authors.forename: Amy S
authors.initials: AS
authors.lastname: Carlos
authors.forename: John K
authors.initials: JK
authors.lastname: Belknap
authors.forename: Peter
authors.initials: P
authors.lastname: Rotwein
authors.forename: Robert F
authors.initials: RF
authors.lastname: Klein
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D003433:Crosses, Genetic; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000378:metabolism; D056726:Genetic Association Studies; D007753:Laboratories; D008126:Lod Score; D008297:Male; D008682:Metatarsal Bones / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D020297:Mice, Congenic; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D055396:Bone Morphogenetic Protein 2; D053773:Transforming Growth Factor beta1