title: Hyperactivation of mTOR critically regulates abnormal osteoclastogenesis in neurofibromatosis Type 1.
abstract: Individuals with nerofibromatosis Type 1 (NF1) frequently suffer a spectrum of bone pathologies, such as abnormal skeletal development (scoliosis, congenital bowing, and congenital pseudoarthroses, etc), lower bone mineral density with increased fracture risk. These skeletal problems may result, in part, from abnormal osteoclastogenesis. Enhanced RAS/PI3K activity has been reported to contribute to abnormal osteoclastogenesis in Nf1 heterozygous (Nf1+/-) mice. However, the specific downstream pathways linked to NF1 abnormal osteoclastogenesis have not been defined. Our aim was to determine whether mammalian target of rapamycin (mTOR) was a key effector responsible for abnormal osteoclastogenesis in NF1. Primary osteoclast-like cells (OCLs) were cultured from Nf1 wild-type (Nf1+/+) and Nf1+/- mice. Compared to Nf1+/+ controls, there were 20% more OCLs induced from Nf1+/- mice. Nf1+/- OCLs were larger and contained more nuclei. Hyperactive mTOR signaling was detected in Nf1+/- OCLs. Inhibition of mTOR signaling by rapamycin in Nf1+/- OCLs abrogated abnormalities in cellular size and number. Moreover, we found that hyperactive mTOR signaling induced abnormal osteoclastogenesis major through hyper-proliferation. Our research suggests that neurofibromin directly regulates osteoclastogenesis through mTOR signaling pathway. Inhibiting mTOR may represent a viable strategy to treat NF1 bone diseases.
authors: West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Junrong
authors: J
authors: Ma
authors: Mi
authors: M
authors: Li
authors: Janet
authors: J
authors: Hock
authors: Xijie
authors: X
authors: Yu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D005838:Genotype; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009456:Neurofibromatosis 1 / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D025542:Neurofibromin 1; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus