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

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 vi...

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Autores principales: Kim, Jung-Min, Yang, Yeon-Suk, Hong, Jaehyoung, Chaugule, Sachin, Chun, Hyonho, van der Meulen, Marjolein CH, Xu, Ren, Greenblatt, Matthew B, Shim, Jae-hyuck
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9417416/
https://www.ncbi.nlm.nih.gov/pubmed/35975983
http://dx.doi.org/10.7554/eLife.78069
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author Kim, Jung-Min
Yang, Yeon-Suk
Hong, Jaehyoung
Chaugule, Sachin
Chun, Hyonho
van der Meulen, Marjolein CH
Xu, Ren
Greenblatt, Matthew B
Shim, Jae-hyuck
author_facet Kim, Jung-Min
Yang, Yeon-Suk
Hong, Jaehyoung
Chaugule, Sachin
Chun, Hyonho
van der Meulen, Marjolein CH
Xu, Ren
Greenblatt, Matthew B
Shim, Jae-hyuck
author_sort Kim, Jung-Min
collection PubMed
description 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.
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spelling pubmed-94174162022-08-27 Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathway Kim, Jung-Min Yang, Yeon-Suk Hong, Jaehyoung Chaugule, Sachin Chun, Hyonho van der Meulen, Marjolein CH Xu, Ren Greenblatt, Matthew B Shim, Jae-hyuck eLife Medicine 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. eLife Sciences Publications, Ltd 2022-08-17 /pmc/articles/PMC9417416/ /pubmed/35975983 http://dx.doi.org/10.7554/eLife.78069 Text en © 2022, Kim et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Medicine
Kim, Jung-Min
Yang, Yeon-Suk
Hong, Jaehyoung
Chaugule, Sachin
Chun, Hyonho
van der Meulen, Marjolein CH
Xu, Ren
Greenblatt, Matthew B
Shim, Jae-hyuck
Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathway
title Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathway
title_full Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathway
title_fullStr Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathway
title_full_unstemmed Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathway
title_short Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathway
title_sort biphasic regulation of osteoblast development via the erk mapk–mtor pathway
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9417416/
https://www.ncbi.nlm.nih.gov/pubmed/35975983
http://dx.doi.org/10.7554/eLife.78069
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