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 Mohammad, Theresa 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
Article numbere46900
JournalPLoS One
Volume7
Issue number11
DOIs
StatePublished - Nov 7 2012

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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

He, Y., Rhodes, S. D., Chen, S., Wu, X., Yuan, J., Yang, X., ... Yang, F. C. (2012). c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions. PLoS One, 7(11), [e46900]. https://doi.org/10.1371/journal.pone.0046900

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; Guise, Theresa; 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, K, Guise, T & Yang, FC 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 ; Guise, Theresa ; 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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