Murine Model for Cystic Fibrosis Bone Disease Demonstrates Osteopenia and Sex-Related Differences in Bone Formation

Pashuck, Troy D; Franz, Sarah E.; Altman, Molly K.; Wasserfall, Clive; Atkinson, Mark A.; Wronski, Thomas J.; Flotte, Terence R.; Stalvey, Michael S.

doi:10.1203/pdr.0b013e3181961e80

Cited by 45 publications

(35 citation statements)

References 45 publications

(64 reference statements)

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“…For example, osteoporosis is a common complication in CF patients and osteopenia has been observed in CF mouse models (14,19,37). Whether this decrease in bone mineral density is directly due to absence of CFTR from cell types found in bone (47) or a secondary effect due to endocrine dysfunction or even perturbations in calcium homeostasis due to absence of CFTR from the gut, kidney (1), or other tissue is unknown.…”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium

Hodges¹,

Grady²,

Mishra³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Maldigestion due to exocrine pancreatic insufficiency leads to intestinal malabsorption and consequent malnutrition, a mechanism proposed to cause growth retardation associated with cystic fibrosis (CF). However, although enzyme replacement therapy combined with increased caloric intake improves weight gain, the effect on stature is not significant, suggesting that growth retardation has a more complex etiology. Mouse models of CF support this, since these animals do not experience exocrine pancreatic insufficiency yet are growth impaired. Cftr absence from the intestinal epithelium has been suggested as a primary source of growth retardation in CF mice, a concept we directly tested by generating mouse models with Cftr selectively inactivated or restored in intestinal epithelium. The relationship between growth and functional characteristics of the intestines, including transepithelial electrophysiology, incidence of intestinal obstruction, and histopathology, were assessed. Absence of Cftr exclusively from intestinal epithelium resulted in loss of cAMP-stimulated short-circuit current, goblet cell hyperplasia, and occurrence of intestinal obstructions but only slight and transient impaired growth. In contrast, specifically restoring Cftr to the intestinal epithelium resulted in restoration of ion transport and completely protected against obstruction and histopathological anomalies, but growth was indistinguishable from CF mice. These results indicate that absence of Cftr in the intestinal epithelium is an important contributor to the intestinal obstruction phenotype in CF but does not correlate with the observed growth reduction in CF.

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Section: Discussionmentioning

confidence: 99%

Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium

Hodges¹,

Grady²,

Mishra³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In contrast, bone density, which shows little relationship to cord blood IGF1 (20), did not differ by genotype. Decreased bone mineral density has been reported in CF mice, but these studies have tended to focus on older mice (21)(22)(23)(24). Whether bone mineral density will decrease with time in CF pigs and whether IGF1 will contribute to this process remain to be determined.…”

Section: Cf Pigs Showmentioning

confidence: 99%

Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth

Rogan¹,

Reznikov

Pezzulo³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

101

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People with cystic fibrosis (CF) exhibit growth defects. That observation has been attributed, in part, to decreased insulin-like growth factor 1 (IGF1) levels, and the reduction has been blamed on malnutrition and pulmonary inflammation. However, patients with CF already have a reduced weight at birth, a manifestation not likely secondary to poor nutrition or inflammation. We found that, like humans, CF pigs were smaller than non-CF littermates and had lower IGF1 levels. To better understand the basis of IGF1 reduction, we studied newborn pigs and found low IGF1 levels within 12 h of birth. Moreover, humerus length and bone mineral content were decreased, consistent with less IGF1 activity in utero. These findings led us to test newborn humans with CF, and we found that they also had reduced IGF1 levels. Discovering lower IGF1 levels in newborn pigs and humans indicates that the decrease is not solely a consequence of malnutrition or pulmonary inflammation and that loss of cystic fibrosis transmembrane conductance regulator function has a more direct effect. Consistent with this hypothesis, we discovered reduced growth hormone release in organotypic pituitary slice cultures of newborn CF pigs. These findings may explain the long-standing observation that CF newborns are smaller than non-CF babies and why some patients with good clinical status fail to reach their growth potential. The results also suggest that measuring IGF1 levels might be of value as a biomarker to predict disease severity or the response to therapeutics. Finally, they raise the possibility that IGF1 supplementation beginning in infancy might be beneficial in CF.

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“…These data raised the hypothesis that the Cftr gene may play a role in cell differentiation and bone matrix maturation ( Table 1). The use of mouse models with a Cftr invalidation or with the F508 mutation in Cftr eliminates other clinical parameters, namely lung disease and chronic malnutrition that are absent in these models [61,62]. Genetic studies in Cftr−/− mice have shown that Cftr invalidation causes low bone mass and altered microarchitecture, a phenotype associated with decreased bone formation and increased bone resorption [61,63,64].…”

Section: Cftr Dysfunction In Bone Cellsmentioning

confidence: 99%

“…The use of mouse models with a Cftr invalidation or with the F508 mutation in Cftr eliminates other clinical parameters, namely lung disease and chronic malnutrition that are absent in these models [61,62]. Genetic studies in Cftr−/− mice have shown that Cftr invalidation causes low bone mass and altered microarchitecture, a phenotype associated with decreased bone formation and increased bone resorption [61,63,64]. More recently, Stalvey and colleagues demonstrated altered osteoblast differentiation with reduced OPG production in cultured calvaria cells from Cftr−/− mice [39].…”

Section: Cftr Dysfunction In Bone Cellsmentioning

confidence: 99%

“…S1P formed by phosphorylation of sphingosine catalysed by two sphingosine kinases (SPHK1 and SPHK2) is a well-known bioactive lipid mediator, playing important roles in many tissue repair processes, including bone regeneration and osseous tissue growth in vivo [87]. It has been recently proposed that Cftr −/− mice treated with intestinal hCFTR (aged 14 weeks) Osteopenia and low BMD in male and female mice [61] F508del-Cftr mice (aged 6, 10 and 14 weeks) Osteopenia, low BMD and decreased bone formation rate in male and female mice [65] F508del-Cftr male mice (aged 6 weeks) treated with miglustat for 4 weeks Improved bone formation rate, bone mass and microarchitecture in the lumbar spine and femur [38] Cftr −/− murine calvarial organ cultures Reduced differentiation and osteoprotegerin production [39] Normal human osteoblasts cultured with the pharmacological CFTR inhibitor CFTR inh-172…”

Section: Cftr Dysfunction In Bone Cellsmentioning

confidence: 99%

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Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

Jacquot

Delion²,

Gangloff³

et al. 2015

Osteoporos Int

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Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone-resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD.

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Murine Model for Cystic Fibrosis Bone Disease Demonstrates Osteopenia and Sex-Related Differences in Bone Formation

Cited by 45 publications

References 45 publications

Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium

Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium

Pigs and humans with cystic fibrosis have reduced insulin-like growth factor 1 (IGF1) levels at birth

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

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