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Persistent Osteopenia in Adult Cystic Fibrosis Transmembrane Conductance Regulator–deficient Mice

¹ Meakins-Christie Laboratories and ² J.T.N. Wong Laboratories for Mineralised Tissue Research, Department of Medicine, McGill University, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to Christina Haston, Ph.D., Meakins-Christie Laboratories, 3626 rue St. Urbain, Montreal, PQ, H2X 2P2 Canada. E-mail: christina.haston{at}mcgill.ca

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.

Key Words: bone disease • lung disease • preclinical model • genetically modified mouse

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Bone disease in patients with cystic fibrosis is multifactorial, but the contribution of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to bone disease remains undefined. What This Study Adds to the Field We show that adult Cftr-deficient mice have low femoral bone mineral density and compromised bone architecture in the absence of other overt disease symptoms. The results suggest that deficiency of Cftr contributes to the osteopenic phenotype of Cftr–/– mice.