Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice

Richa Sharma, Xiaohua Wu, Steven D. Rhodes, Shi Chen, Yongzheng He, Jin Yuan, Jiliang Li, Xianlin Yang, Xiaohong Li, Li Jiang, Edward T. Kim, David A. Stevenson, David Viskochil, Mingjiang Xu, Feng Chun Yang

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Neurobromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to de bilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseu-darthrosis (nonunion fracture).Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progeni-tors andmesenchymal stemcells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPKas a critical pathway underlying the pathogenesis of NF1-associated fracture repair decits. Nf1-decient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase acti-vating-related domain (NF1 GAP-related domain) in vitro is sufcient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1-/- pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-decient murine pro-OBLs. Similarly,MEK inhibition enhancesOBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclastmaturation in Nf1 haploinsufcient bonemarrowmononuclear cells (BMMNCs). Importantly,MEKin-hibitor signicantly improves fracture healing in an NF1 murine model, Col2.3Cre;Nf1ox/2. Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis relatedtoNF1mutations.These studiesprovide evidence for targeting the MAPK pathway to improve bone mass and treat pseudarthrosis in NF1.

Original languageEnglish
Article numberddt333
Pages (from-to)4818-4828
Number of pages11
JournalHuman Molecular Genetics
Volume22
Issue number23
DOIs
StatePublished - Dec 2013

Fingerprint

Tibial Fractures
Mitogen-Activated Protein Kinases
Osteoblasts
Pseudarthrosis
Mitogen-Activated Protein Kinase Kinases
Critical Pathways
Bone and Bones
Inborn Genetic Diseases
Fracture Healing
Metabolic Bone Diseases
GTP Phosphohydrolases
Osteocalcin
Scoliosis
Cell Lineage
Osteoclasts
Osteoporosis
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Sharma, R., Wu, X., Rhodes, S. D., Chen, S., He, Y., Yuan, J., ... Yang, F. C. (2013). Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice. Human Molecular Genetics, 22(23), 4818-4828. [ddt333]. https://doi.org/10.1093/hmg/ddt333

Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice. / Sharma, Richa; Wu, Xiaohua; Rhodes, Steven D.; Chen, Shi; He, Yongzheng; Yuan, Jin; Li, Jiliang; Yang, Xianlin; Li, Xiaohong; Jiang, Li; Kim, Edward T.; Stevenson, David A.; Viskochil, David; Xu, Mingjiang; Yang, Feng Chun.

In: Human Molecular Genetics, Vol. 22, No. 23, ddt333, 12.2013, p. 4818-4828.

Research output: Contribution to journalArticle

Sharma, R, Wu, X, Rhodes, SD, Chen, S, He, Y, Yuan, J, Li, J, Yang, X, Li, X, Jiang, L, Kim, ET, Stevenson, DA, Viskochil, D, Xu, M & Yang, FC 2013, 'Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice', Human Molecular Genetics, vol. 22, no. 23, ddt333, pp. 4818-4828. https://doi.org/10.1093/hmg/ddt333
Sharma, Richa ; Wu, Xiaohua ; Rhodes, Steven D. ; Chen, Shi ; He, Yongzheng ; Yuan, Jin ; Li, Jiliang ; Yang, Xianlin ; Li, Xiaohong ; Jiang, Li ; Kim, Edward T. ; Stevenson, David A. ; Viskochil, David ; Xu, Mingjiang ; Yang, Feng Chun. / Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 23. pp. 4818-4828.
@article{bf86228ddb974405b8e4a2ceb0ed67d8,
title = "Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice",
abstract = "Neurobromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to de bilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseu-darthrosis (nonunion fracture).Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progeni-tors andmesenchymal stemcells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPKas a critical pathway underlying the pathogenesis of NF1-associated fracture repair decits. Nf1-decient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase acti-vating-related domain (NF1 GAP-related domain) in vitro is sufcient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1-/- pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-decient murine pro-OBLs. Similarly,MEK inhibition enhancesOBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclastmaturation in Nf1 haploinsufcient bonemarrowmononuclear cells (BMMNCs). Importantly,MEKin-hibitor signicantly improves fracture healing in an NF1 murine model, Col2.3Cre;Nf1ox/2. Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis relatedtoNF1mutations.These studiesprovide evidence for targeting the MAPK pathway to improve bone mass and treat pseudarthrosis in NF1.",
author = "Richa Sharma and Xiaohua Wu and Rhodes, {Steven D.} and Shi Chen and Yongzheng He and Jin Yuan and Jiliang Li and Xianlin Yang and Xiaohong Li and Li Jiang and Kim, {Edward T.} and Stevenson, {David A.} and David Viskochil and Mingjiang Xu and Yang, {Feng Chun}",
year = "2013",
month = "12",
doi = "10.1093/hmg/ddt333",
language = "English",
volume = "22",
pages = "4818--4828",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "23",

}

TY - JOUR

T1 - Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice

AU - Sharma, Richa

AU - Wu, Xiaohua

AU - Rhodes, Steven D.

AU - Chen, Shi

AU - He, Yongzheng

AU - Yuan, Jin

AU - Li, Jiliang

AU - Yang, Xianlin

AU - Li, Xiaohong

AU - Jiang, Li

AU - Kim, Edward T.

AU - Stevenson, David A.

AU - Viskochil, David

AU - Xu, Mingjiang

AU - Yang, Feng Chun

PY - 2013/12

Y1 - 2013/12

N2 - Neurobromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to de bilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseu-darthrosis (nonunion fracture).Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progeni-tors andmesenchymal stemcells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPKas a critical pathway underlying the pathogenesis of NF1-associated fracture repair decits. Nf1-decient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase acti-vating-related domain (NF1 GAP-related domain) in vitro is sufcient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1-/- pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-decient murine pro-OBLs. Similarly,MEK inhibition enhancesOBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclastmaturation in Nf1 haploinsufcient bonemarrowmononuclear cells (BMMNCs). Importantly,MEKin-hibitor signicantly improves fracture healing in an NF1 murine model, Col2.3Cre;Nf1ox/2. Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis relatedtoNF1mutations.These studiesprovide evidence for targeting the MAPK pathway to improve bone mass and treat pseudarthrosis in NF1.

AB - Neurobromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to de bilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseu-darthrosis (nonunion fracture).Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progeni-tors andmesenchymal stemcells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPKas a critical pathway underlying the pathogenesis of NF1-associated fracture repair decits. Nf1-decient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase acti-vating-related domain (NF1 GAP-related domain) in vitro is sufcient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1-/- pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-decient murine pro-OBLs. Similarly,MEK inhibition enhancesOBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclastmaturation in Nf1 haploinsufcient bonemarrowmononuclear cells (BMMNCs). Importantly,MEKin-hibitor signicantly improves fracture healing in an NF1 murine model, Col2.3Cre;Nf1ox/2. Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis relatedtoNF1mutations.These studiesprovide evidence for targeting the MAPK pathway to improve bone mass and treat pseudarthrosis in NF1.

UR - http://www.scopus.com/inward/record.url?scp=84887520191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887520191&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddt333

DO - 10.1093/hmg/ddt333

M3 - Article

C2 - 23863460

AN - SCOPUS:84887520191

VL - 22

SP - 4818

EP - 4828

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 23

M1 - ddt333

ER -