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The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis

Authors
 Jung-Min Kim  ;  Yeon-Suk Yang  ;  Kwang Hwan Park  ;  Hwanhee Oh  ;  Matthew B Greenblatt  ;  Jae-Hyuck Shim 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol.20(8) : e1803, 2019-04 
Journal Title
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 
Issue Date
2019-04
MeSH
Animals ; Biomarkers ; Bone Development* / genetics ; Bone and Bones / metabolism ; Bone and Bones / pathology ; Cell Differentiation ; Cleidocranial Dysplasia / genetics ; Cleidocranial Dysplasia / metabolism ; Cleidocranial Dysplasia / pathology ; Disease Models, Animal ; Disease Susceptibility ; Extracellular Signal-Regulated MAP Kinases / metabolism* ; Homeostasis* ; Immunohistochemistry ; MAP Kinase Signaling System* ; Mice ; Mice, Knockout ; Osteoblasts / cytology ; Osteoblasts / metabolism ; Osteogenesis / genetics
Keywords
ERK ; MAPK ; MEK1 ; MEK2 ; cleidocranial dysplasia ; osteoblast ; osteopenia
Abstract
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 (Mek1OsxMek2-/-), 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 (Mek1Osx-ERTMek2-/-) 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.
Files in This Item:
T201906292.pdf Download
DOI
10.3390/ijms20081803
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
Yonsei Authors
Park, Kwang Hwan(박광환) ORCID logo https://orcid.org/0000-0002-2110-0559
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175834
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