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

TitleBiphasic regulation of osteoblast development via the ERK MAPK-mTOR pathway.
Publication TypeJournal Article
Year of Publication2022
AuthorsKim J-M, Yang Y-S, Hong J, Chaugule S, Chun H, van der Meulen MCH, Xu R, Greenblatt MB, Shim J-H
Date Published2022 Aug 17
KeywordsAnimals, Extracellular Signal-Regulated MAP Kinases, Mice, Osteoblasts, Osteogenesis, Phosphorylation, TOR Serine-Threonine Kinases

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.

Alternate JournalElife
PubMed ID35975983
PubMed Central IDPMC9417416
Grant ListR01 AR075585 / AR / NIAMS NIH HHS / United States
R21 AR077557 / AR / NIAMS NIH HHS / United States
Related Faculty: 
Matthew B. Greenblatt, M.D., Ph.D.

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