Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The F508del mutation in the cystic fibrosis transmembrane conductance regulator (Cftr) gene is believed to be an independent risk factor for cystic fibrosis-related bone disease. In this study, we evaluated the bone mineral density as well as the histomorphometric parameters of bone formation and bone mass in both F508del-Cftr homozygous mice (F508del Cftr(tm1Eur)) and Cftr(+/+) littermate controls at 6 (prepubertal), 10 (pubertal), and 14 (young adult) weeks of age in both sexes. The bone architecture of F508del Cftr(tm1Eur) and wild-type (WT) littermate mice was evaluated by bone densitometry, microcomputed tomography, and analysis of the dynamic parameters of bone formation. Serum levels of both insulin-like growth factor 1 and osteocalcin also were determined. Reduced bone mineral density, lower femoral bone mass, and altered trabecular bone architecture were observed in F508del Cftr(tm1Eur) mice compared with controls at 6, 10, and 14 weeks of age. A decrease in the bone formation rate in F508del Cftr(tm1Eur) mice was shown compared with control mice, independently of age and sex. In addition, we found lower insulin-like growth factor 1 levels in F508del Cftr(tm1Eur) mice compared with age-matched controls, whereas osteocalcin levels were normal. Severe osteopenia and altered bone architecture were found in young and mature adult F508del Cftr(tm1Eur) mice. Our findings show that the F508del mutation in CFTR impacts trabecular bone mass by reducing bone formation.
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PMID:The F508del mutation in cystic fibrosis transmembrane conductance regulator gene impacts bone formation. 2244 49

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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PMID:Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies. 2643 78