title: Multiple increased osteoclast functions in individuals with neurofibromatosis type 1.
abstract: Skeletal abnormalities including scoliosis, tibial dysplasia, sphenoid wing dysplasia, and decreased bone mineral density (BMD) are associated with neurofibromatosis type 1 (NF1). We report the cellular phenotype of NF1 human-derived osteoclasts and compare the in vitro findings with the clinical phenotype. Functional characteristics (e.g., osteoclast formation, migration, adhesion, resorptive capacity) and cellular mechanistic alterations (e.g., F-actin polymerization, MAPK phosphorylation, RhoGTPase activity) from osteoclasts cultured from peripheral blood of individuals with NF1 (N = 75) were assessed. Osteoclast formation was compared to phenotypic, radiologic, and biochemical data. NF1 osteoprogenitor cells demonstrated increased osteoclast forming capacity. Human NF1-derived osteoclasts demonstrated increased migration, adhesion, and in vitro bone resorption. These activities coincided with increased actin belt formation and hyperactivity in MAPK and RhoGTPase pathways. Although osteoclast formation was increased, no direct correlation of osteoclast formation with BMD, markers of bone resorption, or the clinical skeletal phenotype was observed suggesting that osteoclast formation in vitro cannot directly predict NF1 skeletal phenotypes. While NF1 haploinsufficiency produces a generalized osteoclast gain-in-function and may contribute to increased bone resorption, reduced BMD, and focal skeletal defects associated with NF1, additional and perhaps local modifiers are likely required for the development of skeletal abnormalities in NF1.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stevenson
authors.forename: Jincheng
authors.initials: J
authors.lastname: Yan
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: He
authors.forename: Huijie
authors.initials: H
authors.lastname: Li
authors.forename: Yaling
authors.initials: Y
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Jing
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Dalong
authors.initials: D
authors.lastname: Yang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.forename: Heather
authors.initials: H
authors.lastname: Hanson
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.forename: Karl
authors.initials: K
authors.lastname: Staser
authors.forename: David H
authors.initials: DH
authors.lastname: Viskochil
authors.forename: John C
authors.initials: JC
authors.lastname: Carey
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Lucy
authors.initials: L
authors.lastname: Miller
authors.forename: Kent
authors.initials: K
authors.lastname: Roberson
authors.forename: Laurie
authors.initials: L
authors.lastname: Moyer-Mileur
authors.forename: Menggang
authors.initials: M
authors.lastname: Yu
authors.forename: Elisabeth L
authors.initials: EL
authors.lastname: Schwarz
authors.forename: Marzia
authors.initials: M
authors.lastname: Pasquali
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D007223:Infant; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000473:pathology*; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology
chemical_list: D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases