Neurofibromin deficiency-associated transcriptional dysregulation suggests a novel therapy for tibial pseudoarthrosis in NF1

Nandina Paria, Tae Joon Cho, In Ho Choi, Nobuhiro Kamiya, Kay Kayembe, Rong Mao, Rebecca L. Margraf, Gerlinde Obermosser, Ila Oxendine, David W. Sant, Mi Hyun Song, David A. Stevenson, David H. Viskochil, Carol A. Wise, Harry K W Kim, Jonathan J. Rios

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2636-2642
Number of pages7
JournalJournal of Bone and Mineral Research
Issue number12
StatePublished - Dec 1 2014


  • Cell/tissue signaling-transcription factors
  • Diseases and disorders related to bone-other
  • Human association studies
  • Molecular pathways-development
  • Tumor-induced bone disease

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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