Multiple increased osteoclast functions in individuals with neurofibromatosis type 1

David A. Stevenson, Jincheng Yan, Yongzheng He, Huijie Li, Yaling Liu, Qi Zhang, Yongmin Jing, Zhiping Guo, Wei Zhang, Dalong Yang, Xiaohua Wu, Heather Hanson, Xiaohong Li, Karl Staser, David H. Viskochil, John C. Carey, Shi Chen, Lucy Miller, Kent Roberson, Laurie Moyer-MileurMenggang Yu, Elisabeth L. Schwarz, Marzia Pasquali, Feng Chun Yang

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1050-1059
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume155
Issue number5
DOIs
StatePublished - May 1 2011

Fingerprint

Neurofibromatosis 1
Osteoclasts
Bone Resorption
Bone Density
Phenotype
Actins
Haploinsufficiency
Scoliosis
Polymerization
Phosphorylation

Keywords

  • Bone mineral density
  • Bone resorption
  • Neurofibromatosis type 1
  • Osteoporosis
  • Ras

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Stevenson, D. A., Yan, J., He, Y., Li, H., Liu, Y., Zhang, Q., ... Yang, F. C. (2011). Multiple increased osteoclast functions in individuals with neurofibromatosis type 1. American Journal of Medical Genetics, Part A, 155(5), 1050-1059. https://doi.org/10.1002/ajmg.a.33965

Multiple increased osteoclast functions in individuals with neurofibromatosis type 1. / Stevenson, David A.; Yan, Jincheng; He, Yongzheng; Li, Huijie; Liu, Yaling; Zhang, Qi; Jing, Yongmin; Guo, Zhiping; Zhang, Wei; Yang, Dalong; Wu, Xiaohua; Hanson, Heather; Li, Xiaohong; Staser, Karl; Viskochil, David H.; Carey, John C.; Chen, Shi; Miller, Lucy; Roberson, Kent; Moyer-Mileur, Laurie; Yu, Menggang; Schwarz, Elisabeth L.; Pasquali, Marzia; Yang, Feng Chun.

In: American Journal of Medical Genetics, Part A, Vol. 155, No. 5, 01.05.2011, p. 1050-1059.

Research output: Contribution to journalArticle

Stevenson, DA, Yan, J, He, Y, Li, H, Liu, Y, Zhang, Q, Jing, Y, Guo, Z, Zhang, W, Yang, D, Wu, X, Hanson, H, Li, X, Staser, K, Viskochil, DH, Carey, JC, Chen, S, Miller, L, Roberson, K, Moyer-Mileur, L, Yu, M, Schwarz, EL, Pasquali, M & Yang, FC 2011, 'Multiple increased osteoclast functions in individuals with neurofibromatosis type 1', American Journal of Medical Genetics, Part A, vol. 155, no. 5, pp. 1050-1059. https://doi.org/10.1002/ajmg.a.33965
Stevenson, David A. ; Yan, Jincheng ; He, Yongzheng ; Li, Huijie ; Liu, Yaling ; Zhang, Qi ; Jing, Yongmin ; Guo, Zhiping ; Zhang, Wei ; Yang, Dalong ; Wu, Xiaohua ; Hanson, Heather ; Li, Xiaohong ; Staser, Karl ; Viskochil, David H. ; Carey, John C. ; Chen, Shi ; Miller, Lucy ; Roberson, Kent ; Moyer-Mileur, Laurie ; Yu, Menggang ; Schwarz, Elisabeth L. ; Pasquali, Marzia ; Yang, Feng Chun. / Multiple increased osteoclast functions in individuals with neurofibromatosis type 1. In: American Journal of Medical Genetics, Part A. 2011 ; Vol. 155, No. 5. pp. 1050-1059.
@article{3b76c493c2c94401bb292611f0e05d09,
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.",
keywords = "Bone mineral density, Bone resorption, Neurofibromatosis type 1, Osteoporosis, Ras",
author = "Stevenson, {David A.} and Jincheng Yan and Yongzheng He and Huijie Li and Yaling Liu and Qi Zhang and Yongmin Jing and Zhiping Guo and Wei Zhang and Dalong Yang and Xiaohua Wu and Heather Hanson and Xiaohong Li and Karl Staser and Viskochil, {David H.} and Carey, {John C.} and Shi Chen and Lucy Miller and Kent Roberson and Laurie Moyer-Mileur and Menggang Yu and Schwarz, {Elisabeth L.} and Marzia Pasquali and Yang, {Feng Chun}",
year = "2011",
month = "5",
day = "1",
doi = "10.1002/ajmg.a.33965",
language = "English (US)",
volume = "155",
pages = "1050--1059",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "5",

}

TY - JOUR

T1 - Multiple increased osteoclast functions in individuals with neurofibromatosis type 1

AU - Stevenson, David A.

AU - Yan, Jincheng

AU - He, Yongzheng

AU - Li, Huijie

AU - Liu, Yaling

AU - Zhang, Qi

AU - Jing, Yongmin

AU - Guo, Zhiping

AU - Zhang, Wei

AU - Yang, Dalong

AU - Wu, Xiaohua

AU - Hanson, Heather

AU - Li, Xiaohong

AU - Staser, Karl

AU - Viskochil, David H.

AU - Carey, John C.

AU - Chen, Shi

AU - Miller, Lucy

AU - Roberson, Kent

AU - Moyer-Mileur, Laurie

AU - Yu, Menggang

AU - Schwarz, Elisabeth L.

AU - Pasquali, Marzia

AU - Yang, Feng Chun

PY - 2011/5/1

Y1 - 2011/5/1

N2 - 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.

AB - 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.

KW - Bone mineral density

KW - Bone resorption

KW - Neurofibromatosis type 1

KW - Osteoporosis

KW - Ras

UR - http://www.scopus.com/inward/record.url?scp=79955007125&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955007125&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.33965

DO - 10.1002/ajmg.a.33965

M3 - Article

C2 - 21465658

AN - SCOPUS:79955007125

VL - 155

SP - 1050

EP - 1059

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 5

ER -