Human Molecular Genetics Advance Access published online on August 7, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl208
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1 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202
* To whom correspondence should be addressed. 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, reduced bone mineral density, 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) activity compared to wildtype (WT) MSPC. Nf1+/- MSPC also have fewer senescent cells and have a significantly higher telomerase activity compared to WT MSPC. Nf1+/- MSPC have impaired osteoblast differentiation as determined by alkaline phosphatase (ALP) 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 GRD) 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.
Received May 30, 2006
Revised July 29, 2006
Accepted July 29, 2006
Article
Neurofibromin plays a critical role in modulating osteoblast differentiation of mesenchymal stem/progenitor cells
Xiaohua Wu 1, Selina A. Estwick 1, Shi Chen 1, Menggang Yu 2, Wenyu Ming 1, Todd D. Nebesio 1, Yan Li 1, Jin Yuan 1, Kapur Reuben 3, David Ingram 3, Mervin C. Yoder 3, and Feng-Chun Yang 4 *
2 Department of Medicine/Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana 46202
3 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202
4 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut St., R4/427, Indianapolis, Indiana 46202
Feng-Chun Yang, E-mail: fyang{at}iupui.edu
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