Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 29, Issue 12, Pages 2636-2642Publisher
WILEY-BLACKWELL
DOI: 10.1002/jbmr.2298
Keywords
TUMOR-INDUCED BONE DISEASE; MOLECULAR PATHWAYS-DEVELOPMENT; CELL; TISSUE SIGNALING-TRANSCRIPTION FACTORS; HUMAN ASSOCIATION STUDIES; DISEASES AND DISORDERS RELATED TO BONE-OTHER
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Funding
- Pediatric Orthopaedic Society of North America
- Department of Defense [W81XWH-11-1-250]
- Shriners Hospital for Children (Salt Lake City, UT, USA)
- Texas Scottish Rite Hospital for Children
- University of Utah Clinical Genetics Research Program (CGRP)
- National Center for Research Resources
- National Center for Advancing Translational Sciences at the National Institutes of Health [UL1RR025764]
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001105]
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Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in NF1. Among the earliest manifestations is tibial pseudoarthrosis and persistent nonunion after fracture. To further understand the pathogenesis of pseudoarthrosis and the underlying bone remodeling defect, pseudoarthrosis tissue and cells cultured from surgically resected pseudoarthrosis tissue from NF1 individuals were analyzed using whole-exome and whole-transcriptome sequencing as well as genomewide microarray analysis. Genomewide analysis identified multiple genetic mechanisms resulting in somatic biallelic NF1 inactivation; no other genes with recurring somatic mutations were identified. Gene expression profiling identified dysregulated pathways associated with neurofibromin deficiency, including phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Unlike aggressive NF1-associated malignancies, tibial pseudoarthrosis tissue does not harbor a high frequency of somatic mutations in oncogenes or other tumor-suppressor genes, such as p53. However, gene expression profiling indicates that pseudoarthrosis tissue has a tumor-promoting transcriptional pattern, despite lacking tumorigenic somatic mutations. Significant overexpression of specific cancer-associated genes in pseudoarthrosis highlights a potential for receptor tyrosine kinase inhibitors to target neurofibromin-deficient pseudoarthrosis and promote proper bone remodeling and fracture healing. (c) 2014 American Society for Bone and Mineral Research
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