CFTR-deficient pigs display alterations of bone microarchitecture and composition at birth
Julien Braux1, Marie-Laure Jourdain1, Christine Guillaume1
1Université de Reims Champagne Ardenne, BIOS EA 4691, Biomatériaux et Inflammation en site osseux, SFR CAP-Santé (FED 4231), 1, Avenue du Maréchal Juin, 51097 Reims, France.
Insights
Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function in pigs alters bone microstructure and composition at birth. This suggests bone defects in cystic fibrosis may be a primary issue, not secondary to inflammation.
Area of Science:
- Bone biology
- Genetics
- Physiology
Background:
- Cystic fibrosis (CF) is caused by absent or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR).
- CF patients exhibit bone issues like osteopenia, even before severe lung disease, hinting at developmental origins.
- Studying CFTR's role in bone is challenging in humans, necessitating animal models.
Purpose of the Study:
- To investigate the direct impact of CFTR absence on bone development and composition.
- To compare bone parameters in newborn CFTR-deficient pigs versus wild-type littermates.
Main Methods:
- Micro-computed tomography (μCT) was used to assess femoral cortical and trabecular bone morphology and microstructure.
- Raman microspectroscopy analyzed the chemical composition of the bone.
- Studies were conducted on both male and female CFTR knockout (CFTR-/-) pigs and their wild-type (WT) littermates.
Main Results:
- CFTR-/- pigs exhibited altered bone integrity, with reduced cortical thickness and increased cortical porosity compared to WT pigs.
- Trabecular bone in CFTR-/- pigs showed increased chemical heterogeneity, a higher carbonate/phosphate ratio, and enhanced mineral crystallinity.
- These bone composition changes were observed in both male and female newborn pigs.
Conclusions:
- The absence of CFTR directly impacts bone composition and metabolism in newborn pigs.
- These findings suggest that bone defects in cystic fibrosis patients may be a primary consequence of CFTR dysfunction, rather than secondary to chronic inflammation or infection.
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.
Related Concept Videos
01:24Bone Formation by Endochondral Ossification
01:29Bone Formation by Intramembranous Ossification
The process begins when mesenchymal cells in the embryonic skeleton gather together and differentiate into osteogenic cells, which then develop into ...
01:29Bone Disorders
Bone deposition is also affected by the levels of sex hormones like estrogen and testosterone that promote osteoblast activity and bone matrix synthesis. When the level of these hormones decreases due to aging, it causes a reduction in bone deposition. As a result, bone resorption by osteoclasts...