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Reduced bone length, growth plate thickness, bone content, and IGF-I as a model for poor growth in the CFTR-deficient
Michael S Stalvey1,2, Viktoria Havasi1,2, Katherine L Tuggle2,3
1Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States of America.
Insights
Young cystic fibrosis (CF) rats lacking functional CFTR show impaired growth and bone development. Reduced growth plate size and lower IGF-I levels suggest CFTR is crucial for normal bone growth, independent of lung or pancreatic issues.
Area of Science:
- Bone Biology
- Genetics
- Pediatrics
Background:
- Reduced growth and osteopenia are common in cystic fibrosis (CF).
- The mechanisms underlying growth reduction in CF are not fully understood.
- Improved weight and height correlate with better lung function and overall health in CF patients.
Purpose of the Study:
- To investigate growth in young CF rats using a novel CFTR knockout rat model.
- To evaluate femur length, bone microarchitecture, growth plate characteristics, and serum IGF-I concentrations in CF animals.
Main Methods:
- Measurement of femur length as a growth surrogate in wild-type (WT) and Cftr-/- rats.
- Micro-computed tomography (micro-CT) for quantitative bone analysis.
- Bone histomorphometry, growth plate analysis, and serum IGF-I concentration comparison.
Main Results:
- Cftr-/- rats exhibited reduced femur length in both males and females compared to WT.
- Bone microarchitecture (trabecular and cortical) was adversely affected in Cftr-/- rats.
- Growth plate thickness, hypertrophic zone thickness, and mean hypertrophic cell volume were reduced, alongside severely decreased serum IGF-I concentrations.
Conclusions:
- Young Cftr-/- rats displayed reduced growth and bone content even without overt lung or pancreatic disease.
- Decreased growth plate size and lower IGF-I concentrations indicate the mechanistic basis for the observed growth phenotype.
- These findings highlight the intrinsic role of CFTR in maintaining normal bone growth, independent of other clinical factors.
Background:
Reduced growth and osteopenia are common in individuals with cystic fibrosis (CF). Additionally, improved weight and height are associated with better lung function and overall health in the disease. Mechanisms for this reduction in growth are not understood. We utilized a new CFTR knockout rat to evaluate growth in young CF animals, via femur length, microarchitecture of bone and growth plate, as well as serum IGF-I concentrations.
Methods:
Femur length was measured in wild-type (WT) and SD-CFTRtm1sage (Cftr-/-) rats, as a surrogate marker for growth. Quantitative bone parameters in Cftr-/- and WT rats were measured by micro computed tomography (micro-CT). Bone histomorphometry and cartilaginous growth plates were analyzed. Serum IGF-I concentrations were also compared.
Results:
Femur length was reduced in both Cftr-/- male and female rats compared to WT. Multiple parameters of bone microarchitecture (of both trabecular and cortical bone) were adversely affected in Cftr-/- rats. There was a reduction in overall growth plate thichkness in both male and female Cftr-/- rats, as well as hypertrophic zone thickness and mean hypertrophic cell volume in male rats, indicating abnormal growth characteristics at the plate. Serum IGF-I concentrations were severely reduced in Cftr-/- rats compared to WT littermates.
Conclusions:
Despite absence of overt lung or pancreatic disease, reduced growth and bone content were readily detected in young Cftr-/- rats. Reduced size of the growth plate and decreased IGF-I concentrations suggest the mechanistic basis for this phenotype. These findings appear to be intrinsic to the CFTR deficient state and independent of significant clinical confounders, providing substantive evidence for the importance of CFTR on maintinaing normal bone growth.
