title: Quantitative trait locus that determines the cross-sectional shape of the femur in SAMP6 and SAMP2 mice.
abstract: We segregated a QTL on chromosome 11 that affects femoral cross-sectional shape during growth by generating a congenic strain and an additional 16 subcongenic strains of the senescence-accelerated mouse strain, SAMP6. The QTL region was narrowed down to a 10.0-Mbp region.
  
  
  BACKGROUND
  Genetic background is known to affect bone characteristics. However, little is known about how polymorphic genes modulate bone shape. In a previous study using SAMP2 and SAMP6 mice, we reported a quantitative trait locus (QTL) on chromosome (Chr) 11 that had significant linkage to peak relative bone mass in terms of cortical thickness index (CTI) in male mice. We named it Pbd1. Here we aimed to clarify the effects of Pbd1 on skeletal phenotype in male mice and to narrow down the QTL region.
  
  
  METHODS
  We generated a congenic strain named P6.P2-Pbd1(b), carrying a 39-cM SAMP2-derived Chr11 interval on a SAMP6 genetic background. Sixteen subcongenic strains with smaller overlapping intervals on the SAMP6 background were generated from P6.P2-Pbd1(b) to narrow the region of interest. The effects of Pbd1 on bone properties were determined. Gene expression analysis of all candidate genes in Pbd1 was performed using real-time RT-PCR.
  
  
  RESULTS
  The CTI of strain P6.P2-Pbd1(b) at 16 wk was higher than that of SAMP6. This was not caused by differences in cortical thickness but by cross-sectional shape. Morphological analysis by microCT revealed that the femoral cross-sectional shape of P6.P2-Pbd1(b) (and the other subcongenic strains with higher CTI or bone area fraction [BA/TA]) was more compressed anteroposteriorly than that of SAMP6, which was associated with superior mechanical properties. This feature was formed during bone modeling up to 16 wk of age. Subcongenic strains with a higher CTI showed significant increases in endocortical mineral apposition rate and significant reductions in periosteal mineral apposition rate at 8 wk compared with those of the SAMP6. The Pbd1 locus was successfully narrowed down to a 10.0-Mbp region, and the expression analysis suggested a candidate gene, Cacng4.
  
  
  CONCLUSIONS
  The Pbd1 affects femoral cross-sectional shape by regulating the rate of endocortical and periosteal bone formation of the femur during postnatal growth.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Bungo
authors.initials: B
authors.lastname: Otsuki
authors.forename: Takuro
authors.initials: T
authors.lastname: Matsumura
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Shimizu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mori
authors.forename: Shuzo
authors.initials: S
authors.lastname: Okudaira
authors.forename: Rika
authors.initials: R
authors.lastname: Nakanishi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Higuchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Tadao
authors.initials: T
authors.lastname: Tsuboyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics*; D015220:Calcium Channels / Q000235:genetics*; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics*; D005269:Femur / Q000033:anatomy & histology / Q000502:physiology*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D040641:Quantitative Trait Loci
chemical_list: C499759:Cacng4 protein, mouse; D015220:Calcium Channels