Persistent osteopenia in adult cystic fibrosis transmembrane conductance regulator-deficient mice.

RATIONALE: A loss of function mutation in the cystic fibrosis transmembrane conductance regulator gene is believed to be an independent risk factor for bone disease in patients with cystic fibrosis. OBJECTIVES: The objective of this work was to use congenic mice as a preclinical model to examine the bone phenotype of Cftr(-/-) mice and control littermates at 8, 12, and 28 weeks of age. METHODS: The bone phenotype of control and Cftr(-/-) mice was evaluated by quantitative imaging, histologic and histomorphometric analyses, and serum levels of bone biomarkers. MEASUREMENTS AND MAIN RESULTS: At 12 weeks of age, Cftr(-/-) mice were smaller, had lower bone mineral density, cortical bone thinning, and altered trabecular architecture compared with Cftr(+/+) or Cftr(+/-) control mice. In skeletally mature 28-week-old mice, there were persistent deficits in cortical and trabecular bone structure in Cftr(-/-) mice despite significant, quantifiable improvements. Cftr(-/-) mice also had lower serum insulin-like growth factor-I levels at 12 weeks of age than did control mice, whereas parathyroid hormone and 25-hydroxyvitamin D levels were not significantly different. CONCLUSIONS: Persistent osteopenia and structural abnormalities in adult Cftr(-/-) mice, in the absence of overt respiratory and gastrointestinal disease, suggest that loss of Cftr function has a direct impact on bone metabolism in Cftr(-/-) mice that is not sex specific or subject to haplotype insufficiency.

X chromosome transmission ratio distortion in Cftr +/- intercross-derived mice.

BACKGROUND: Cystic fibrosis (CF) mice, created with a genetically engineered mutation in the Cystic fibrosis transmembrane conductance regulator (Cftr) gene, may develop intestinal plugs which limit their survival past weaning. In a studied population of genetically mixed CF mice differences in allelic ratios at particular loci, between surviving CF mice and mice with the lethal intestinal defect, were used to map cystic fibrosis modifier gene one, Cfm1. Using this approach, we previously identified an X chromosome locus which may influence the survival to weaning of C57BL/6J x BALB/cJ F2 CF mice. We also detected two regions of transmission ratio distortion, independent of Cftr genotype, in a limited dataset. To investigate these findings, in this study we have genotyped 1208 three-week old F2 mice, and 186 day E15.5 embryos, derived from a congenic (C57BL/6J x BALB/cJ) F1 Cftr +/- intercross, for the putative distortion regions. RESULTS: An excess of homozygous BALB genotypes, compared to Mendelian expectations, was detected on chromosomes 5 (p = 5.7 x 10-15) and X (p = 3.0 x 10-35) in three-week old female mice but transmission ratio distortion was not evident in the tested region of chromosome 3 (p = 0.39). Significant pre-weaning lethality of CF mice occurred as 11.3% (137/1208) of the three-week old offspring were identified as CF mice. X chromosome genotypes were not, however, distorted in the female CF mice (p = 0.62), thus the significant non-Mendelian inheritance of this locus was dependent on CF status. The survival of CF embryos to day E15.5 was consistent with Mendelian expectations (42/186 = 23%), demonstrating the loss of CF mice to have occurred between E15.5 and three weeks of age. The excess of X chromosome homozygous BALB genotypes was recorded in female embryos (p = 0.0048), including CF embryos, indicating the distortion to be evident at this age. CONCLUSION: Two of three previously suggested loci of transmission ratio distortion were replicated as distorted in this mouse cross. The non-Mendelian inheritance of X chromosome genotypes implicates this region in the survival to weaning of non-CF mice.