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 Scopus citations

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

    Fingerprint

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., Jiang, L., Li, X., Takahashi, N., Xu, M., Mohammad, K. S., Guise, T. A., & 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