CFTR deletion affects mouse osteoblasts in a gender‐specific manner

Abstract

Advancements in research and care have contributed to increase life expectancy of individuals with cystic fibrosis (CF). With increasing age comes a greater likelihood of developing CF bone disease, a comorbidity characterized by a low bone mass and impaired bone quality, which displays gender differences in severity. However, pathophysiological mechanisms underlying this gender difference have never been thoroughly investigated. We used bone marrow-derived osteoblasts and osteoclasts from Cftr +/+ and Cftr −/− mice to examine whether the impact of CF transmembrane conductance regulator (CFTR) deletion on cellular differentiation and functions differed between genders. To determine whether in vitro findings translated into in vivo observations, we used imaging techniques and three-point bending testing. In vitro studies revealed no osteoclast-autonomous defect but impairment of osteoblast differentiation and functions and aberrant responses to various stimuli in cells isolated from Cftr −/− females only. Compared with wild-type controls, knockout mice exhibited a trabecular osteopenic phenotype that was more pronounced in Cftr −/− males than Cftr −/− females. Bone strength was reduced to a similar extent in knockout mice of both genders. In conclusion, we find a trabecular bone phenotype in Cftr −/− mice that was slightly more pronounced in males than females, which is reminiscent of the situation found in patients. However, at the osteoblast level, the pathophysiological mechanisms underlying this phenotype differ between males and females, which may underlie gender differences in the way bone marrow-derived osteoblasts behave in absence of CFTR.

Hydrokinetic pancreatic function and insulin secretion are moduled by Cl− uniporter Slc26a9 in mice

“…The mechanisms explaining why female bone marrow cells are more responsive to the lack of CFTR than male cells in vitro are unknown but possibly relate to epigenetic processes. 36 In summary, the present work demonstrates significantly reduced pancreatic fluid secretory rates and impaired glucose tolerance in female slc26a9 −/− mice, particularly at young age. Because of the extremely high, male-predominant, excess perinatal mortality, the above-noticed female preponderance of the pancreatic functional defects may be in part explained by breedingdifficulty-related less perfectly matched conditions for breeding of male than female mice, and needs to be reinvestigated.…”

Cystic Fibrosis Bone Disease: The Interplay between CFTR Dysfunction and Chronic Inflammation

“…CFTR is expressed by several cells in the organism, namely by hematopoietic progenitors in the bone marrow and osteoclasts, as well as osteoblasts, osteocytes and chondrocytes and their progenitors [ 88 , 89 , 90 , 91 ]. Therefore, altered CFTR function may compromise osteoblast and osteoclast development and bone remodeling.…”

Cystic Fibrosis and Genotype-Dependent Therapy: Is There a Need for a Sex-Specific Therapy?

“…Estrogen has been shown to modulate drug pharmacokinetics, 132 with differences in drug metabolism likely contributing to drug efficacy. 128 For example, both ivacaftor (VX-770) and lumacaftor (VX-809) are potent inducers of the cytochrome P450 system, 133,134 and since there are well-characterized gender differences in the expression of P450 enzymes, 135 it is not unreasonable to suppose that the half-lives of drugs in patients may vary with gender. For example, Ambien, zolpidem, is metabolized by the p450 system much slower in females than males and therefore has a longer half-life.…”

“…Thus, while there is fairly strong evidence of a gender gap in CF outcomes, it is unlikely that it comes down to something as simple as estrogen. The increasing understanding that sex chromosomes express regulators that can modulate expression from autosomes, 128 suggests that it is likely a complex interplay of differential gene expression and signaling that impacts gender differences in CF. How easily such interplay can be unraveled to identify key pharmacological targets is not certain.…”