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, David Ingram, D. Clapp, J. M. Hock

Research output: Contribution to journalArticle

83 Citations (Scopus)

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

Fingerprint

Neurofibromin 1
Osteoblasts
Bone and Bones
Osteopontin
Neurofibromatosis 1
Signal Transduction
Homeostasis
Neurofibromatosis 1 Genes
Haploinsufficiency
Bone Matrix
Heterozygote
Osteogenesis
Femur
Osteoporosis
Alkaline Phosphatase
Proteins
Bone Marrow
Apoptosis
Phenotype
Messenger RNA

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Hematology

Cite this

Yu, X., Chen, S., Potter, O. L., Murthy, S. M., Li, J., Pulcini, J. M., ... 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

Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning. / Yu, X.; Chen, S.; Potter, O. L.; Murthy, S. M.; Li, J.; Pulcini, J. M.; Ohashi, N.; Winata, T.; Everett, E. T.; Ingram, David; Clapp, D.; Hock, J. M.

In: Bone, Vol. 36, No. 5, 05.2005, p. 793-802.

Research output: Contribution to journalArticle

Yu, X, Chen, S, Potter, OL, Murthy, SM, Li, J, Pulcini, JM, Ohashi, N, Winata, T, Everett, ET, Ingram, D, Clapp, D & Hock, JM 2005, 'Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning', Bone, vol. 36, no. 5, pp. 793-802. https://doi.org/10.1016/j.bone.2005.01.022
Yu X, Chen S, Potter OL, Murthy SM, Li J, Pulcini JM et al. Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning. Bone. 2005 May;36(5):793-802. https://doi.org/10.1016/j.bone.2005.01.022
Yu, X. ; Chen, S. ; Potter, O. L. ; Murthy, S. M. ; Li, J. ; Pulcini, J. M. ; Ohashi, N. ; Winata, T. ; Everett, E. T. ; Ingram, David ; Clapp, D. ; Hock, J. M. / Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning. In: Bone. 2005 ; Vol. 36, No. 5. pp. 793-802.
@article{8f638a2c09db40d08ca7521caf32c8d8,
title = "Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning",
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.",
keywords = "Genetically modified mice, Neurofibromatosis type I, Osteopontin, Osteoprogenitor, Ras",
author = "X. Yu and S. Chen and Potter, {O. L.} and Murthy, {S. M.} and J. Li and Pulcini, {J. M.} and N. Ohashi and T. Winata and Everett, {E. T.} and David Ingram and D. Clapp and Hock, {J. M.}",
year = "2005",
month = "5",
doi = "10.1016/j.bone.2005.01.022",
language = "English",
volume = "36",
pages = "793--802",
journal = "Bone",
issn = "8756-3282",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - Neurofibromin and its inactivation of Ras are prerequisites for osteoblast functioning

AU - Yu, X.

AU - Chen, S.

AU - Potter, O. L.

AU - Murthy, S. M.

AU - Li, J.

AU - Pulcini, J. M.

AU - Ohashi, N.

AU - Winata, T.

AU - Everett, E. T.

AU - Ingram, David

AU - Clapp, D.

AU - Hock, J. M.

PY - 2005/5

Y1 - 2005/5

N2 - 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.

AB - 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.

KW - Genetically modified mice

KW - Neurofibromatosis type I

KW - Osteopontin

KW - Osteoprogenitor

KW - Ras

UR - http://www.scopus.com/inward/record.url?scp=20944447547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20944447547&partnerID=8YFLogxK

U2 - 10.1016/j.bone.2005.01.022

DO - 10.1016/j.bone.2005.01.022

M3 - Article

C2 - 15804420

AN - SCOPUS:20944447547

VL - 36

SP - 793

EP - 802

JO - Bone

JF - Bone

SN - 8756-3282

IS - 5

ER -