title: Mammalian target of rapamycin inhibitor abrogates abnormal osteoclastogenesis in neurofibromatosis type 1.
abstract: BACKGROUND
  Neurofibromatosis type 1 (NF1) is the most common genetic syndrome predisposing patients to various tumors due to dysregulation of the Ras signaling pathway. Recent research has shown NF1 patients also suffer a spectrum of bone pathologies. The pathogenesis of NF1 bone diseases is largely unknown. There is no current treatment. By Nf1 heterozygote (Nf1+/-) mice and Nf1 conditional knockout mice, we and other groups demonstrated abnormal osteoblast and osteoclast function due to dysregulation of Ras signaling. However, the specific downstream effector pathways linked to NF1 abnormal osteoblastogenesis and osteoclastogenesis have not been defined. In this study, we investigated the Ras downstream effector related with NF1 bone disease.
  
  
  METHODS
  We used Nf1+/+ and Nf1+/- mice as normal and NF1 models. Bone stromal cells extracted from Nf1+/+ and Nf1+/- mice were induced osteoclasts. The osteoclast cell was stained by tartrate resistant acid phosphatase staining. The osteoclast cell number was counted and the surface area of osteoclast cells was calculated under the microscope. The mRNA of mammalian target of rapamycin (mTOR) was determined by quantitative reverse-transcription-polymerase chain reaction. The presence of ribosomal protein S6 kinase was determined by Western blotting.
  
  
  RESULTS
  Compared with Nf1+/+ mice, Nf1+/- mice had about 20% more of osteoclast cells. These osteoclast cells were larger in size with more nuclei. Hyperactive mTOR was detected in Nf1+/- osteoclast cells. Inhibition of mTOR signaling by rapamycin in Nf1+/- osteoclasts abrogated abnormalities in cellular size and number.
  
  
  CONCLUSIONS
  mTOR pathway inhibition may represent a viable therapy for NF1 bone diseases.
authors.affiliation: Haidian Maternal and Child Health Hospital, Beijing 100080, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Li-hui
authors.initials: LH
authors.lastname: Wei
authors.forename: Guo-lin
authors.initials: GL
authors.lastname: Chai
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D009456:Neurofibromatosis 1 / Q000188:drug therapy*; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus