Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning

X. Yu, S. Chen, O. L. Potter, S. M. Murthy, J. Li, J. M. Pulcini, N. Ohashi, T. Winata, E. T. Everett, D. Ingram, W. D. Clapp, J. M. Hock

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Skeletal problems and osteoporosis occur in up to 50% affected neurofibromatosis type 1 (NF1) humans. Inactivation of neurofibromin results in deregulation of Ras signal transduction. Little is known of bone biology in humans with NF1. The goal of our work was to determine if loss-of-function of Nf1 gene was associated with altered bone homeostasis and Ras signal transduction. Because homozygous Nf1 mice are embryonically lethal, heterozygote Nf1 (Nf1+/-) male mice were used to investigate skeletal phenotypes and osteoprogenitor functions, using standard in vivo and in vitro assays. We found that bone mass and geometry of Nf1+/- mice did not differ from wild type controls, despite a trend to less bone formation. Nf1+/- committed osteoprogenitors from femur metaphysis exhibited premature apoptosis and higher proliferation. Ras signaling was activated in primary Nf1+/- bone marrow-inducible osteoprogenitors. Inducible osteoprogenitors exhibited lower induction of osteoblast differentiation, assessed as alkaline phosphatase positive CFU-f. A screen of osteoblast marker genes showed a selective increase in osteopontin (OPN) mRNA and protein expression in these cells. OPN protein was increased in Nf1+/- bone, especially in cortical bone matrix. Because bone cell abnormalities in Nf1 haploinsufficiency were detected in vitro, redundant pathways must compensate for the deregulation of Ras signaling in vivo to maintain normal bone mass and function in vivo. Our in vitro data revealed that neurofibromin and its control of Ras signaling are required for osteoprogenitor homeostasis.

Original languageEnglish (US)
Pages (from-to)793-802
Number of pages10
JournalBone
Volume36
Issue number5
DOIs
StatePublished - May 2005

Keywords

  • Genetically modified mice
  • Neurofibromatosis type I
  • Osteopontin
  • Osteoprogenitor
  • Ras

ASJC Scopus subject areas

  • Physiology
  • Hematology

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    Yu, X., Chen, S., Potter, O. L., Murthy, S. M., Li, J., Pulcini, J. M., Ohashi, N., Winata, T., Everett, E. T., Ingram, D., Clapp, W. D., & Hock, J. M. (2005). Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning. Bone, 36(5), 793-802. https://doi.org/10.1016/j.bone.2005.01.022