The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1

Xiaohua Wu, Shi Chen, Yongzheng He, Steven D. Rhodes, Khalid Mohammad, Xiaohong Li, Xianlin Yang, Li Jiang, Grzegorz Nalepa, Paige Snider, Alexander Robling, D. Clapp, Simon Conway, Theresa Guise, Feng Chun Yang

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre +;Nf1 flox/- and Col2.3Cre +;Nf1 flox/-mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.

Original languageEnglish
Article numbere24917
JournalPLoS One
Volume6
Issue number9
DOIs
StatePublished - Sep 29 2011

Fingerprint

Spontaneous Fractures
Neurofibromatosis 1
stem cells
Repair
animal models
skeletal development
tumor suppressor genes
osteoblasts
osteoporosis
bone marrow cells
mice
genetic disorders
germ cells
Bone
Fracture Healing
Adoptive Transfer
bones
Mesenchymal Stromal Cells
mutation
Osteoblasts

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1. / Wu, Xiaohua; Chen, Shi; He, Yongzheng; Rhodes, Steven D.; Mohammad, Khalid; Li, Xiaohong; Yang, Xianlin; Jiang, Li; Nalepa, Grzegorz; Snider, Paige; Robling, Alexander; Clapp, D.; Conway, Simon; Guise, Theresa; Yang, Feng Chun.

In: PLoS One, Vol. 6, No. 9, e24917, 29.09.2011.

Research output: Contribution to journalArticle

Wu, Xiaohua ; Chen, Shi ; He, Yongzheng ; Rhodes, Steven D. ; Mohammad, Khalid ; Li, Xiaohong ; Yang, Xianlin ; Jiang, Li ; Nalepa, Grzegorz ; Snider, Paige ; Robling, Alexander ; Clapp, D. ; Conway, Simon ; Guise, Theresa ; Yang, Feng Chun. / The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1. In: PLoS One. 2011 ; Vol. 6, No. 9.
@article{6f1d9895830043a2bb3f90261e052797,
title = "The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1",
abstract = "Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre +;Nf1 flox/- and Col2.3Cre +;Nf1 flox/-mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.",
author = "Xiaohua Wu and Shi Chen and Yongzheng He and Rhodes, {Steven D.} and Khalid Mohammad and Xiaohong Li and Xianlin Yang and Li Jiang and Grzegorz Nalepa and Paige Snider and Alexander Robling and D. Clapp and Simon Conway and Theresa Guise and Yang, {Feng Chun}",
year = "2011",
month = "9",
day = "29",
doi = "10.1371/journal.pone.0024917",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1

AU - Wu, Xiaohua

AU - Chen, Shi

AU - He, Yongzheng

AU - Rhodes, Steven D.

AU - Mohammad, Khalid

AU - Li, Xiaohong

AU - Yang, Xianlin

AU - Jiang, Li

AU - Nalepa, Grzegorz

AU - Snider, Paige

AU - Robling, Alexander

AU - Clapp, D.

AU - Conway, Simon

AU - Guise, Theresa

AU - Yang, Feng Chun

PY - 2011/9/29

Y1 - 2011/9/29

N2 - Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre +;Nf1 flox/- and Col2.3Cre +;Nf1 flox/-mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.

AB - Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre +;Nf1 flox/- and Col2.3Cre +;Nf1 flox/-mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.

UR - http://www.scopus.com/inward/record.url?scp=80053311813&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053311813&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0024917

DO - 10.1371/journal.pone.0024917

M3 - Article

C2 - 21980365

AN - SCOPUS:80053311813

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e24917

ER -