CFTR-deficient pigs display alterations of bone microarchitecture and composition at birth

Abstract

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 (μCT), 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.

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

“…The main effects of CFTR mutations are diminished ability to interact with other proteins and faulty chloride channel function, which ultimately influence bone cell differentiation [ 79 ]. CFTR deficiency alters porosity and chemical composition in the bones of newborn pigs [ 80 ], as well as reducing bone length, growth plate thickness, bone content and insulin-like growth factor-I in CFTR-knockout rats [ 81 ]. In patients with CF, CFTR mutation may impact NF-κB and Wnt signalling, resulting in disruption to osteoblast differentiation as well as decreased bone formation and increased bone resorption [ 79 , 82 ].…”

Bone Cells Differentiation: How CFTR Mutations May Rule the Game of Stem Cells Commitment?

“…Loss of CFTR protein or/and its chloride channel function has a detrimental impact on bone cells. Recent studies in CFTR-deficient new-born pigs showed high porosity of cortical bones and altered chemical composition of the trabecular bones (Braux et al, 2020). Cftr−/− mice display severe osteopenia in both trabecular and cortical bone (Dif et al, 2004).…”

Approaching prosthesis infection environment: Development of an innovative in vitro Staphylococcus aureus biofilm model

“…Regarding bones samples, the number of CFU was correlated with the weight of the samples after determination of a linear correlation between weight and available bone surface using micro-computed tomography (Skyscan 1076, Bruker Optics, Germany) ( Supplementary Fig. S2 ) [ 30 ]. For each experiment, at least four biological repeats were performed.…”