Neurofibromin Deficiency‐Associated Transcriptional Dysregulation Suggests a Novel Therapy for Tibial Pseudoarthrosis in NF1. (December 2014)

• Record Type: Journal Article
• Authors: Paria, Nandina; Cho, Tae‐Joon; Choi, In Ho; Kamiya, Nobuhiro; Kayembe, Kay; Mao, Rong; Margraf, Rebecca L; Obermosser, Gerlinde; Oxendine, Ila; Sant, David W; Song, Mi Hyun; Stevenson, David A; Viskochil, David H; Wise, Carol A; Kim, Harry KW; Rios, Jonathan J
• Is Part Of: Journal of bone and mineral research. Volume 29:Number 12(2014:Dec.)
• Page Start: 2636
• Page End: 2642
• Publication Date: 2014-12
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2298
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2298-sec-0001" sec-type="section"> <p>Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in <italic>NF1</italic>. 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 <italic>NF1</italic> 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. © 2014 American Society for Bone and Mineral Research</p> </sec> </abstract>