Biphasic regulation of osteoblast development via the ERK MAPK-mTOR pathway

  1. Jung-Min Kim
  2. Yeon-Suk Yang
  3. Jaehyoung Hong
  4. Sachin Chaugule
  5. Hyonho Chun
  6. Marjolein CH van der Meulen
  7. Ren Xu
  8. Matthew B Greenblatt
  9. Jae-hyuck Shim  Is a corresponding author
  1. University of Massachusetts Medical School, United States
  2. Korea Advanced Institute of Science and Technology, Republic of Korea
  3. Cornell University, United States
  4. Xiamen University, China
  5. Weill Cornell, United States

Abstract

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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all the figures.

Article and author information

Author details

  1. Jung-Min Kim

    Department of Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  2. Yeon-Suk Yang

    Department of Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  3. Jaehyoung Hong

    Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    No competing interests declared.
  4. Sachin Chaugule

    Department of Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  5. Hyonho Chun

    Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    No competing interests declared.
  6. Marjolein CH van der Meulen

    Meinig School of Biomedical Engineering, Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6637-9808
  7. Ren Xu

    State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6578-4553
  8. Matthew B Greenblatt

    Department of Pathology and Laboratory Medicine, Weill Cornell, New York, United States
    Competing interests
    No competing interests declared.
  9. Jae-hyuck Shim

    Department of Medicine, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    jaehyuck.shim@umassmed.edu
    Competing interests
    Jae-hyuck Shim, is a scientific co-founder of the AAVAA Therapeutics and holds equity in this company. These pose no conflicts for this study..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4947-3293

Funding

NIH-NIAMS (R21AR077557)

  • Jae-hyuck Shim

AAVAA Therapeutics

  • Jae-hyuck Shim

Burroughs Wellcome Fund

  • Matthew B Greenblatt

NIH-NIAMS (R01AR075585)

  • Matthew B Greenblatt

Novartis Institutes for Biomedical Research Global Scholars Award

  • Matthew B Greenblatt

Pershing Square Sohn Cancer Research Alliance award

  • Matthew B Greenblatt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (A2564) of the University of Massachusetts Chan Medical School. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Massachusetts Chan Medical School (A2564).

Reviewing Editor

  1. Hiroshi Takayanagi, The University of Tokyo, Japan

Publication history

  1. Preprint posted: January 24, 2022 (view preprint)
  2. Received: February 22, 2022
  3. Accepted: August 16, 2022
  4. Accepted Manuscript published: August 17, 2022 (version 1)
  5. Version of Record published: August 26, 2022 (version 2)

Copyright

© 2022, Kim et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jung-Min Kim
  2. Yeon-Suk Yang
  3. Jaehyoung Hong
  4. Sachin Chaugule
  5. Hyonho Chun
  6. Marjolein CH van der Meulen
  7. Ren Xu
  8. Matthew B Greenblatt
  9. Jae-hyuck Shim
(2022)
Biphasic regulation of osteoblast development via the ERK MAPK-mTOR pathway
eLife 11:e78069.
https://doi.org/10.7554/eLife.78069

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