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A3868 - CFTR-Deficient Pigs Have Altered Bone Microarchitecture and Elevated Closed Cortical Porosity at Birth
Author Block: F. Velard1, M. Jourdain1, I. Caballero-Posadas2, N. Winter2, M. Si-Tahar3, N. Klymiuk4, S. C. Gangloff1, J. Jacquot1, J. Braux1; 1EA 4691 BIOS, University of Reims Champagne-Ardenne, Reims, France, 2UMR1282 ISP, INRA, Nouzilly, France, 3Centre d’Etude des Pathologies Respiratoires, UMR1100, Inserm, Tours, France, 4Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universitat Munchen, Munich, Germany.
Background: People with cystic fibrosis exhibit growth defects and brittle bones. That observation has been attributed, in part, to malnutrition and chronic pulmonary inflammation. We tested the hypothesis that disruption of the cystic fibrosis transmembrane conductance regulator (Cftr) gene directly affects bone microarchitecture and integrity by studying bone of newborn Cftr-/- pigs. Methods: We examined femoral cortical and trabecular bones of Cftr-/- pigs less than 24h after birth using micro computed tomography (μ CT, Skyscan 1076, Bruker). Scans were performed with the following settings: tube voltage, 80 kV; tube current, 0.125 mA; and voxel size, 17 x 17 x 17 μm (x, y, z). Three-dimensional images were reconstructed and analysed using the NRecon GPU version and CTAn (Bruker) software programs, respectively. The cortical bone porosity and structure were defined using a 3.4 mm wide region centered on the middle of the femur. A total of 37 newborn Cftr-/- piglets (24 males and 13 females) and 18 newborn Cftr+/+ piglets (8 males and 10 females) was subjected to μCT scan. Results: Compared to newborn Cftr+/+ pig controls, Cftr-/- femoral bone exhibited significantly lower total volume (TV), bone volume (BV) and bone volume density (BV/TV) but only in females. However, the Cftr-/- bone mineral density (BMD) in trabecular and cortical tissues was significantly reduced in both sexes, compared to Cftr+/+ piglets. Interestingly, focusing at the porosity of cortical bone in Cftr-/- pigs as a determinant of bone fragility associated with high fracture risk, we observed higher closed porosity with a marked increase of closed pore surface in cortical bone of Cftr-/- pigs (+18,7% for males and +48% for females). These results suggest a lower bone remodelling, lower interconnectivity within the vascular network, and increased bone fragility in Cftr-/- animals. No significant difference was observed in the open cortical porosity, whatever the gender. Conclusion: Altogether, these data highlight the critical regulatory role of CFTR in bone development and maintenance, and suggest that some bone defects in people with cystic fibrosis are likely primary. This work was, in part, supported by Vertex Inc. and the French Association Vaincre la Mucoviscidose.