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The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is ass...

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Autores principales: Kim, Jung-Min, Yang, Yeon-Suk, Park, Kwang Hwan, Oh, Hwanhee, Greenblatt, Matthew B., Shim, Jae-Hyuck
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514701/
https://www.ncbi.nlm.nih.gov/pubmed/31013682
http://dx.doi.org/10.3390/ijms20081803
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author Kim, Jung-Min
Yang, Yeon-Suk
Park, Kwang Hwan
Oh, Hwanhee
Greenblatt, Matthew B.
Shim, Jae-Hyuck
author_facet Kim, Jung-Min
Yang, Yeon-Suk
Park, Kwang Hwan
Oh, Hwanhee
Greenblatt, Matthew B.
Shim, Jae-Hyuck
author_sort Kim, Jung-Min
collection PubMed
description Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1(Osx)Mek2(−/−)), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1(Osx-ERT)Mek2(−/−)) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and β-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation.
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spelling pubmed-65147012019-05-30 The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis Kim, Jung-Min Yang, Yeon-Suk Park, Kwang Hwan Oh, Hwanhee Greenblatt, Matthew B. Shim, Jae-Hyuck Int J Mol Sci Article Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1(Osx)Mek2(−/−)), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1(Osx-ERT)Mek2(−/−)) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and β-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation. MDPI 2019-04-12 /pmc/articles/PMC6514701/ /pubmed/31013682 http://dx.doi.org/10.3390/ijms20081803 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, Jung-Min
Yang, Yeon-Suk
Park, Kwang Hwan
Oh, Hwanhee
Greenblatt, Matthew B.
Shim, Jae-Hyuck
The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis
title The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis
title_full The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis
title_fullStr The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis
title_full_unstemmed The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis
title_short The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis
title_sort erk mapk pathway is essential for skeletal development and homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514701/
https://www.ncbi.nlm.nih.gov/pubmed/31013682
http://dx.doi.org/10.3390/ijms20081803
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