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Human Molecular Genetics Advance Access originally published online on August 7, 2006
Human Molecular Genetics 2006 15(19):2837-2845; doi:10.1093/hmg/ddl208
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Neurofibromin plays a critical role in modulating osteoblast differentiation of mesenchymal stem/progenitor cells

Xiaohua Wu1,4, Selina A. Estwick1,4, Shi Chen1,4, Menggang Yu3, Wenyu Ming1,4, Todd D. Nebesio1,4, Yan Li1,4, Jin Yuan1,4, Reuben Kapur1,2,4, David Ingram1,2,4, Mervin C. Yoder1,2,4 and Feng-Chun Yang1,4,*

1 Department of Pediatrics, 2 Department of Biochemistry and Molecular Biology, 3 Department of Medicine/Biostatistics and 4 Herman B. Wells Center for Pediatric Research and Indiana University School of Medicine, Cancer Research Institute, 1044 W. Walnut Street, R4/427 Indianapolis, IN 46202, USA

* To whom correspondence should be addressed. Tel: +1 3172744178; Fax: +1 3172748679; Email: fyang{at}iupui.edu

Received May 30, 2006; Accepted July 29, 2006

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1, a pandemic autosomal dominant genetic disorder with an incidence of 1:3000. Individuals with NF1 have a variety of malignant and non-malignant manifestations, including skeletal manifestations, such as osteoporosis, scoliosis and short statures. However, the mechanism(s) underlying the osseous manifestations in NF1 are poorly understood. In the present study, utilizing Nf1 haploinsufficient (+/–) mice, we demonstrate that Nf1+/– mesenchymal stem/progenitor cells (MSPC) have increased proliferation and colony forming unit-fibroblast (CFU-F) capacity compared with wild-type (WT) MSPC. Nf1+/– MSPC also have fewer senescent cells and have a significantly higher telomerase activity compared with WT MSPC. Nf1+/– MSPC have impaired osteoblast differentiation as determined by alkaline phosphatase staining, and confirmed by single CFU-F replating assays. The impaired osteoblast differentiation in Nf1+/– MSPC is consistent with the reduced expression of osteoblast markers at the mRNA level, including osteocalcin and osteonectin. Importantly, re-expression of the full-length NF1 GTPase activating related domain (NF1 GAP-related domain) is sufficient to restore the impaired osteoblast differentiation in Nf1+/– MSPC. Taken together, our results suggest that neurofibromin plays a crucial role in modulating MSPC differentiation into osteoblasts, and the defect in osteoblast differentiation may contribute at least in part to the osseous abnormalities seen in individuals with NF1.


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