title: c-Fms signaling mediates neurofibromatosis Type-1 osteoclast gain-in-functions.
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 p21(Ras) 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.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: He
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rhodes
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: Xianlin
authors.initials: X
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Xianqi
authors.initials: X
authors.lastname: Li
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D025542:Neurofibromin 1; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases