BACKGROUNDNeurofibromatosis 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.

METHODSWe 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.

RESULTSCompared 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.

CONCLUSIONmTOR pathway inhibition may represent a viable therapy for NF1 bone diseases.