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

15 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

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions'. Together they form a unique fingerprint.

  • 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