Reduced bone length, growth plate thickness, bone content, and IGF-I as a model for poor growth in the CFTR-deficient rat

Stalvey, Michael S.; Havasi, Viktória; Tuggle, Katherine L.; Wang, Dezhi; Birket, Susan E.; Rowe, Steven M.; Sorscher, Eric J.

doi:10.1371/journal.pone.0188497

Cited by 25 publications

(16 citation statements)

References 38 publications

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“…CFTR G542X knockin rats demonstrated severe CF manifestations and developmental defects. CF-related abnormalities included reduced growth, aberrant tooth enamel, and meconium ileus ( Figure 1 ), similar to observations in CF rodent models and patients ( Wright et al, 1996 ; Arquitt et al, 2002 ; Meyerholz et al, 2010 ; Tuggle et al, 2014 ; Stalvey et al, 2017 ). Reduced CFTR expression and activity was evident in multiple organs ( Figures 2–4 ).…”

Section: Discussionsupporting

confidence: 78%

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A Novel G542X CFTR Rat Model of Cystic Fibrosis Is Sensitive to Nonsense Mediated Decay

et al. 2020

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Nonsense mutations that lead to the insertion of a premature termination codon (PTC) in the cystic fibrosis transmembrane conductance regulator (CFTR) transcript affect 11% of patients with cystic fibrosis (CF) worldwide and are associated with severe disease phenotype. While CF rat models have contributed significantly to our understanding of CF disease pathogenesis, there are currently no rat models available for studying CF nonsense mutations. Here we created and characterized the first homozygous CF rat model that bears the CFTR G542X nonsense mutation in the endogenous locus using CRISPR/Cas9 gene editing. In addition to displaying severe CF manifestations and developmental defects such as reduced growth, abnormal tooth enamel, and intestinal obstruction, CFTR G542X knockin rats demonstrated an absence of CFTR function in tracheal and intestinal sections as assessed by nasal potential difference and transepithelial short-circuit current measurements. Reduced CFTR mRNA levels in the model further suggested sensitivity to nonsense-mediated decay, a pathway elicited by the presence of PTCs that degrades the PTC-bearing transcripts and thus further diminishes the level of CFTR protein. Although functional restoration of CFTR was observed in G542X rat tracheal epithelial cells in response to single readthrough agent therapy, therapeutic efficacy was not observed in G542X knockin rats in vivo. The G542X rat model provides an invaluable tool for the identification and in vivo validation of potential therapies for CFTR nonsense mutations.

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Section: Discussionsupporting

confidence: 78%

“…CFTR G542X rats displayed development-associated consequences similar to those seen in CFTR knockout rats ( Tuggle et al, 2014 ; Stalvey et al, 2017 ). Marked growth retardation in homozygous rats was observed after 21 days of age, although body sizes between groups appeared similar at birth.…”

Section: Resultsmentioning

confidence: 80%

A Novel G542X CFTR Rat Model of Cystic Fibrosis Is Sensitive to Nonsense Mediated Decay

et al. 2020

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“…While CF rats do not spontaneously develop lung or pancreatic disease during their first 6-weeks of life, they are a good model for investigating bone growth and its direct link to CFTR, without the presence of other disease manifestations such as airway disease. Accordingly, Stalvey et al (2017) examined the role of CFTR loss on bone growth using young Cftr -/- rats by measuring their femur length, bone histomorphometry and cartilaginous growth plates as well as the concentration of serum IGF-I. Deficiency in IGF-I can cause changes in cartilage growth.…”

Section: Lung and Intestine Observations In A Recent Cystic Fibrosis mentioning

confidence: 99%

“…They found that in absence of the CFTR gene, rats show reduced growth and bone content. Also, IGF-I concentration in the serum of Cftr -/- rats (a marker also used in non-CF children with bone disease) is decreased, which may explain changes in the growth plate (Stalvey et al, 2017).…”

Section: Lung and Intestine Observations In A Recent Cystic Fibrosis mentioning

confidence: 99%

Animal Models in the Pathophysiology of Cystic Fibrosis

2019

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Our understanding of the multiorgan pathology of cystic fibrosis (CF) has improved impressively during the last decades, but we still lack a full comprehension of the disease progression. Animal models have greatly contributed to the elucidation of specific mechanisms involved in CF pathophysiology and the development of new therapies. Soon after the cloning of the CF transmembrane conductance regulator (CFTR) gene in 1989, the first mouse model was generated and this model has dominated in vivo CF research ever since. Nonetheless, the failure of murine models to mirror human disease severity in the pancreas and lung has led to the generation of larger animal models such as pigs and ferrets. The following review presents and discusses data from the current animal models used in CF research.

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“… 2018 ), reduced growth plate thickness (Stalvey et al. 2017 ), and increased cortical porosity (Osima et al. 2017 ) support the incidence of compromised bone quality in diabetic subjects.…”

Section: Introductionmentioning

confidence: 96%