PMID- 35975983
OWN - NLM
STAT- MEDLINE
DCOM- 20220829
LR  - 20230504
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 11
DP  - 2022 Aug 17
TI  - Biphasic regulation of osteoblast development via the ERK MAPK-mTOR pathway.
LID - 10.7554/eLife.78069 [doi]
LID - e78069
AB  - Emerging evidence supports that osteogenic differentiation of skeletal 
      progenitors is a key determinant of overall bone formation and bone mass. Despite 
      extensive studies showing the function of mitogen-activated protein kinases 
      (MAPKs) in osteoblast differentiation, none of these studies show in vivo 
      evidence of a role for MAPKs in osteoblast maturation subsequent to lineage 
      commitment. Here, we describe how the extracellular signal-regulated kinase (ERK) 
      pathway in osteoblasts controls bone formation by suppressing the mechanistic 
      target of rapamycin (mTOR) pathway. We also show that, while ERK inhibition 
      blocks the differentiation of osteogenic precursors when initiated at an early 
      stage, ERK inhibition surprisingly promotes the later stages of osteoblast 
      differentiation. Accordingly, inhibition of the ERK pathway using a small 
      compound inhibitor or conditional deletion of the MAP2Ks Map2k1 (MEK1) and Map2k2 
      (MEK2), in mature osteoblasts and osteocytes, markedly increased bone formation 
      due to augmented osteoblast differentiation. Mice with inducible deletion of the 
      ERK pathway in mature osteoblasts also displayed similar phenotypes, 
      demonstrating that this phenotype reflects continuous postnatal inhibition of 
      late-stage osteoblast maturation. Mechanistically, ERK inhibition increases 
      mitochondrial function and SGK1 phosphorylation via mTOR2 activation, which leads 
      to osteoblast differentiation and production of angiogenic and osteogenic factors 
      to promote bone formation. This phenotype was partially reversed by inhibiting 
      mTOR. Our study uncovers a surprising dichotomy of ERK pathway functions in 
      osteoblasts, whereby ERK activation promotes the early differentiation of 
      osteoblast precursors, but inhibits the subsequent differentiation of committed 
      osteoblasts via mTOR-mediated regulation of mitochondrial function and SGK1.
CI  - (c) 2022, Kim et al.
FAU - Kim, Jung-Min
AU  - Kim JM
AUID- ORCID: 0000-0002-9072-4293
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      United States.
FAU - Yang, Yeon-Suk
AU  - Yang YS
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      United States.
FAU - Hong, Jaehyoung
AU  - Hong J
AD  - Department of Mathematical Sciences, Korea Advanced Institute of Science and 
      Technology, Daejeon, Republic of Korea.
FAU - Chaugule, Sachin
AU  - Chaugule S
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      United States.
FAU - Chun, Hyonho
AU  - Chun H
AD  - Department of Mathematical Sciences, Korea Advanced Institute of Science and 
      Technology, Daejeon, Republic of Korea.
FAU - van der Meulen, Marjolein C H
AU  - van der Meulen MCH
AUID- ORCID: 0000-0001-6637-9808
AD  - Meinig School of Biomedical Engineering and Sibley School of Mechanical & 
      Aerospace Engineering, Cornell University, Ithaca, United States.
AD  - Research Division, Hospital for Special Surgery, New York, United States.
FAU - Xu, Ren
AU  - Xu R
AUID- ORCID: 0000-0001-6578-4553
AD  - State Key Laboratory of Cellular Stress Biology, School of Medicine, Xiamen 
      University, Fujian, China.
AD  - Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of 
      Medicine, Xiamen University, Xiamen, Fujian, China.
FAU - Greenblatt, Matthew B
AU  - Greenblatt MB
AD  - Research Division, Hospital for Special Surgery, New York, United States.
AD  - Department of Pathology and Laboratory Medicine, Weill Cornell, New York, United 
      States.
FAU - Shim, Jae-Hyuck
AU  - Shim JH
AUID- ORCID: 0000-0002-4947-3293
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      United States.
AD  - Horae Gene Therapy Center, Worcester, United States.
AD  - Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan 
      Medical School, Worcester, Worcester, United States.
LA  - eng
GR  - R01 AR075585/AR/NIAMS NIH HHS/United States
GR  - R21 AR077557/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220817
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - *Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Mice
MH  - Osteoblasts/metabolism
MH  - *Osteogenesis
MH  - Phosphorylation
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
PMC - PMC9417416
OTO - NOTNLM
OT  - ERK
OT  - MEK
OT  - mTOR
OT  - medicine
OT  - mouse
OT  - osteoblast
COIS- JK, YY, JH, SC, HC, Mv, RX, MG No competing interests declared, JS is a 
      scientific co-founder of the AAVAA Therapeutics and holds equity in this company. 
      These pose no conflicts for this study
EDAT- 2022/08/18 06:00
MHDA- 2022/08/30 06:00
PMCR- 2022/08/17
CRDT- 2022/08/17 08:53
PHST- 2022/02/22 00:00 [received]
PHST- 2022/08/16 00:00 [accepted]
PHST- 2022/08/18 06:00 [pubmed]
PHST- 2022/08/30 06:00 [medline]
PHST- 2022/08/17 08:53 [entrez]
PHST- 2022/08/17 00:00 [pmc-release]
AID - 78069 [pii]
AID - 10.7554/eLife.78069 [doi]
PST - epublish
SO  - Elife. 2022 Aug 17;11:e78069. doi: 10.7554/eLife.78069.