Neurofibromatosis type 1 gene haploinsufficiency reduces AP-1 gene expression without abrogating the anabolic effect of parathyroid hormone

X. Yu, J. Milas, N. Watanabe, N. Rao, S. Murthy, O. L. Potter, M. J. Wenning, D. Clapp, J. M. Hock

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Approximately 50% of neurofibromatosis type 1 (NF1) patients exhibit skeletal pathology, such as premature osteoporosis or pseudoarthroses. Loss of neurofibromin deregulates Ras signal transduction to affect generation of mitogen-activated protein kinase and Akt, both of which have been implicated in parathyroid hormone (PTH) anabolic mechanisms. Our aim was to determine if loss of neurofibromin impaired the anabolic effect of PTH on bone mass. Nf1 heterozygote (Nf1+/-) and wild type (Nf1+/+) mice were treated with recombinant human PTH1-34 or vehicle once daily for 3-28 days. PTH enhanced mRNA expression of c-fos, junB, and fra2 in the distal femur metaphyses of both genotypes; expression of these transcripts was consistently lower in PTH-treated Nf1+/- mice. Despite lowered c-fos expression in Nf1+/- mice, PTH increased bone mass equivalently in both genotypes by 28 days. Ex vivo, Nf1 heterozygosity was associated with increased inducible osteoclasts in PTH-treated bone marrow cells and impairment of the actin stress fiber and cyclic adenosine monophosphate response to PTH in osteoprogenitors. Lower c-fos expression was previously thought to abrogate PTH responsiveness. Our results suggest crosstalk might occur between Ras signal transduction and the protein kinase A pathway in Nf1+/- mice. Ras signal transduction does not appear to be essential for the anabolic actions of PTH on bone. Because PTH was effective in the absence of Nf1, it may offer a useful approach to treat osteoporosis in NF1 patients.

Original languageEnglish
Pages (from-to)162-170
Number of pages9
JournalCalcified Tissue International
Volume78
Issue number3
DOIs
StatePublished - Mar 2006

Fingerprint

Neurofibromatosis 1 Genes
Haploinsufficiency
Anabolic Agents
Neurofibromatosis 1
Transcription Factor AP-1
Parathyroid Hormone
Gene Expression
Neurofibromin 1
Signal Transduction
Bone and Bones
Osteoporosis
Genotype
Stress Fibers
Pseudarthrosis
Osteoclasts
Heterozygote
Cyclic AMP-Dependent Protein Kinases
Mitogen-Activated Protein Kinases
Bone Marrow Cells
Cyclic AMP

Keywords

  • c-fos
  • Mouse
  • Neurofibromatosis type 1
  • Parathyroid hormone

ASJC Scopus subject areas

  • Endocrinology

Cite this

Neurofibromatosis type 1 gene haploinsufficiency reduces AP-1 gene expression without abrogating the anabolic effect of parathyroid hormone. / Yu, X.; Milas, J.; Watanabe, N.; Rao, N.; Murthy, S.; Potter, O. L.; Wenning, M. J.; Clapp, D.; Hock, J. M.

In: Calcified Tissue International, Vol. 78, No. 3, 03.2006, p. 162-170.

Research output: Contribution to journalArticle

Yu, X. ; Milas, J. ; Watanabe, N. ; Rao, N. ; Murthy, S. ; Potter, O. L. ; Wenning, M. J. ; Clapp, D. ; Hock, J. M. / Neurofibromatosis type 1 gene haploinsufficiency reduces AP-1 gene expression without abrogating the anabolic effect of parathyroid hormone. In: Calcified Tissue International. 2006 ; Vol. 78, No. 3. pp. 162-170.
@article{4c1c990e9ba24aecad4d885167d25ef2,
title = "Neurofibromatosis type 1 gene haploinsufficiency reduces AP-1 gene expression without abrogating the anabolic effect of parathyroid hormone",
abstract = "Approximately 50{\%} of neurofibromatosis type 1 (NF1) patients exhibit skeletal pathology, such as premature osteoporosis or pseudoarthroses. Loss of neurofibromin deregulates Ras signal transduction to affect generation of mitogen-activated protein kinase and Akt, both of which have been implicated in parathyroid hormone (PTH) anabolic mechanisms. Our aim was to determine if loss of neurofibromin impaired the anabolic effect of PTH on bone mass. Nf1 heterozygote (Nf1+/-) and wild type (Nf1+/+) mice were treated with recombinant human PTH1-34 or vehicle once daily for 3-28 days. PTH enhanced mRNA expression of c-fos, junB, and fra2 in the distal femur metaphyses of both genotypes; expression of these transcripts was consistently lower in PTH-treated Nf1+/- mice. Despite lowered c-fos expression in Nf1+/- mice, PTH increased bone mass equivalently in both genotypes by 28 days. Ex vivo, Nf1 heterozygosity was associated with increased inducible osteoclasts in PTH-treated bone marrow cells and impairment of the actin stress fiber and cyclic adenosine monophosphate response to PTH in osteoprogenitors. Lower c-fos expression was previously thought to abrogate PTH responsiveness. Our results suggest crosstalk might occur between Ras signal transduction and the protein kinase A pathway in Nf1+/- mice. Ras signal transduction does not appear to be essential for the anabolic actions of PTH on bone. Because PTH was effective in the absence of Nf1, it may offer a useful approach to treat osteoporosis in NF1 patients.",
keywords = "c-fos, Mouse, Neurofibromatosis type 1, Parathyroid hormone",
author = "X. Yu and J. Milas and N. Watanabe and N. Rao and S. Murthy and Potter, {O. L.} and Wenning, {M. J.} and D. Clapp and Hock, {J. M.}",
year = "2006",
month = "3",
doi = "10.1007/s00223-005-0201-x",
language = "English",
volume = "78",
pages = "162--170",
journal = "Calcified Tissue International",
issn = "0171-967X",
publisher = "Springer Verlag",
number = "3",

}

TY - JOUR

T1 - Neurofibromatosis type 1 gene haploinsufficiency reduces AP-1 gene expression without abrogating the anabolic effect of parathyroid hormone

AU - Yu, X.

AU - Milas, J.

AU - Watanabe, N.

AU - Rao, N.

AU - Murthy, S.

AU - Potter, O. L.

AU - Wenning, M. J.

AU - Clapp, D.

AU - Hock, J. M.

PY - 2006/3

Y1 - 2006/3

N2 - Approximately 50% of neurofibromatosis type 1 (NF1) patients exhibit skeletal pathology, such as premature osteoporosis or pseudoarthroses. Loss of neurofibromin deregulates Ras signal transduction to affect generation of mitogen-activated protein kinase and Akt, both of which have been implicated in parathyroid hormone (PTH) anabolic mechanisms. Our aim was to determine if loss of neurofibromin impaired the anabolic effect of PTH on bone mass. Nf1 heterozygote (Nf1+/-) and wild type (Nf1+/+) mice were treated with recombinant human PTH1-34 or vehicle once daily for 3-28 days. PTH enhanced mRNA expression of c-fos, junB, and fra2 in the distal femur metaphyses of both genotypes; expression of these transcripts was consistently lower in PTH-treated Nf1+/- mice. Despite lowered c-fos expression in Nf1+/- mice, PTH increased bone mass equivalently in both genotypes by 28 days. Ex vivo, Nf1 heterozygosity was associated with increased inducible osteoclasts in PTH-treated bone marrow cells and impairment of the actin stress fiber and cyclic adenosine monophosphate response to PTH in osteoprogenitors. Lower c-fos expression was previously thought to abrogate PTH responsiveness. Our results suggest crosstalk might occur between Ras signal transduction and the protein kinase A pathway in Nf1+/- mice. Ras signal transduction does not appear to be essential for the anabolic actions of PTH on bone. Because PTH was effective in the absence of Nf1, it may offer a useful approach to treat osteoporosis in NF1 patients.

AB - Approximately 50% of neurofibromatosis type 1 (NF1) patients exhibit skeletal pathology, such as premature osteoporosis or pseudoarthroses. Loss of neurofibromin deregulates Ras signal transduction to affect generation of mitogen-activated protein kinase and Akt, both of which have been implicated in parathyroid hormone (PTH) anabolic mechanisms. Our aim was to determine if loss of neurofibromin impaired the anabolic effect of PTH on bone mass. Nf1 heterozygote (Nf1+/-) and wild type (Nf1+/+) mice were treated with recombinant human PTH1-34 or vehicle once daily for 3-28 days. PTH enhanced mRNA expression of c-fos, junB, and fra2 in the distal femur metaphyses of both genotypes; expression of these transcripts was consistently lower in PTH-treated Nf1+/- mice. Despite lowered c-fos expression in Nf1+/- mice, PTH increased bone mass equivalently in both genotypes by 28 days. Ex vivo, Nf1 heterozygosity was associated with increased inducible osteoclasts in PTH-treated bone marrow cells and impairment of the actin stress fiber and cyclic adenosine monophosphate response to PTH in osteoprogenitors. Lower c-fos expression was previously thought to abrogate PTH responsiveness. Our results suggest crosstalk might occur between Ras signal transduction and the protein kinase A pathway in Nf1+/- mice. Ras signal transduction does not appear to be essential for the anabolic actions of PTH on bone. Because PTH was effective in the absence of Nf1, it may offer a useful approach to treat osteoporosis in NF1 patients.

KW - c-fos

KW - Mouse

KW - Neurofibromatosis type 1

KW - Parathyroid hormone

UR - http://www.scopus.com/inward/record.url?scp=33645292604&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645292604&partnerID=8YFLogxK

U2 - 10.1007/s00223-005-0201-x

DO - 10.1007/s00223-005-0201-x

M3 - Article

C2 - 16525748

AN - SCOPUS:33645292604

VL - 78

SP - 162

EP - 170

JO - Calcified Tissue International

JF - Calcified Tissue International

SN - 0171-967X

IS - 3

ER -