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Braux, Julien; Jourdain, Marie-Laure; Guillaume, Christine; Untereiner, Valerie; Piot, Olivier; Baehr, Andrea; Klymiuk, Nikolai; Winter, Nathalie; Berri, Mustapha; Buzoni-Gatel, Dominique; Caballero, Ignaccio; Guillon, Antoine; Si-Tahar, Mustapha; Jacquot, Jacky and Velard, Frederic (2020): CFTR-deficient pigs display alterations of bone microarchitecture and composition. In: Journal of Cystic Fibrosis, Vol. 19, No. 3: pp. 466-475

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Background: The lack of cystic fibrosis transmembrane conductance regulator (CFTR) function causes cystic fibrosis (CF), predisposing to severe lung disease, reduced growth and osteopenia. Both reduced bone content and strength are increasingly recognized in infants with CF before the onset of significant lung disease, suggesting a developmental origin and a possible role in bone disease pathogenesis. The role of CFTR in bone metabolism is unclear and studies on humans are not feasible. Deletion of CFTR in pigs (CFTR (-/-) pigs) displays at birth severe malformations similar to humans in the intestine, respiratory tract, pancreas, liver, and male reproductive tract. Methods: We compared bone parameters of CFTR (-/-) male and female pigs with those of their wild-type (WT) littermates at birth. Morphological and microstructural properties of femoral cortical and trabecular bone were evaluated using micro-computed tomography (mu CT), and their chemical compositions were examined using Raman microspectroscopy. Results: The integrity of the CFTR (-/-) bone was altered due to changes in its microstructure and chemical composition in both sexes. Low cortical thickness and high cortical porosity were found in CFTR (-/-) pigs compared to sex-matched WT littermates. Moreover, an increased chemical composition heterogeneity associated with higher carbonate/phosphate ratio and higher mineral crystallinity was found in CFTR (-/-) trabecular bone, but not in CFTR (-/-) cortical bone. Conclusions: The loss of CFTR directly alters the bone composition and metabolism of newborn pigs. Based on these findings, we speculate that bone defects in patients with CF could be a primary, rather than a secondary consequence of inflammation and infection. (C) 2019 The Author(s). Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

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