c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions

Yongzheng He, Steven D. Rhodes, Shi Chen, Xiaohua Wu, Jin Yuan, Xianlin Yang, Li Jiang, Xianqi Li, Naoyuki Takahashi, Mingjiang Xu, Khalid S. Mohammad, Theresa A. Guise, Feng-Chun Yang

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Skeletal abnormalities including osteoporosis and osteopenia occur frequently in both pediatric and adult neurofibromatosis type 1 (NF1) patients. NF1 (Nf1) haploinsufficient osteoclasts and osteoclast progenitors derived from both NF1 patients and Nf1+/- mice exhibit increased differentiation, migration, and bone resorptive capacity in vitro, mediated by hyperactivation of p21Ras in response to limiting concentrations of macrophage-colony stimulating factor (M-CSF). Here, we show that M-CSF binding to its receptor, c-Fms, results in increased c-Fms activation in Nf1+/- osteoclast progenitors, mediating multiple gain-in-functions through the downstream effectors Erk1/2 and p90RSK. PLX3397, a potent and selective c-Fms inhibitor, attenuated M-CSF mediated Nf1+/- osteoclast migration by 50%, adhesion by 70%, and pit formation by 60%. In vivo, we administered PLX3397 to Nf1+/- osteoporotic mice induced by ovariectomy (OVX) and evaluated changes in bone mass and skeletal architecture. We found that PLX3397 prevented bone loss in Nf1+/--OVX mice by reducing osteoclast differentiation and bone resorptive activity in vivo. Collectively, these results implicate the M-CSF/c-Fms signaling axis as a critical pathway underlying the aberrant functioning of Nf1 haploinsufficient osteoclasts and may provide a potential therapeutic target for treating NF1 associated osteoporosis and osteopenia.

Original languageEnglish (US)
Article numbere46900
JournalPLoS One
Volume7
Issue number11
DOIs
StatePublished - Nov 7 2012
Externally publishedYes

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osteoclasts
Neurofibromatosis 1
Osteoclasts
macrophage colony-stimulating factor
Macrophage Colony-Stimulating Factor
Bone
bones
osteopenia
Bone and Bones
Metabolic Bone Diseases
osteoporosis
Osteoporosis
mice
Pediatrics
Critical Pathways
ovariectomy
Ovariectomy
adhesion
Adhesion
Chemical activation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions. / He, Yongzheng; Rhodes, Steven D.; Chen, Shi; Wu, Xiaohua; Yuan, Jin; Yang, Xianlin; Jiang, Li; Li, Xianqi; Takahashi, Naoyuki; Xu, Mingjiang; Mohammad, Khalid S.; Guise, Theresa A.; Yang, Feng-Chun.

In: PLoS One, Vol. 7, No. 11, e46900, 07.11.2012.

Research output: Contribution to journalArticle

He, Y, Rhodes, SD, Chen, S, Wu, X, Yuan, J, Yang, X, Jiang, L, Li, X, Takahashi, N, Xu, M, Mohammad, KS, Guise, TA & Yang, F-C 2012, 'c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions', PLoS One, vol. 7, no. 11, e46900. https://doi.org/10.1371/journal.pone.0046900
He, Yongzheng ; Rhodes, Steven D. ; Chen, Shi ; Wu, Xiaohua ; Yuan, Jin ; Yang, Xianlin ; Jiang, Li ; Li, Xianqi ; Takahashi, Naoyuki ; Xu, Mingjiang ; Mohammad, Khalid S. ; Guise, Theresa A. ; Yang, Feng-Chun. / c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions. In: PLoS One. 2012 ; Vol. 7, No. 11.
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