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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-08-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/78069 |
| _version_ | 1811252363603738624 |
|---|---|
| author | Jung-Min Kim Yeon-Suk Yang Jaehyoung Hong Sachin Chaugule Hyonho Chun Marjolein CH van der Meulen Ren Xu Matthew B Greenblatt Jae-hyuck Shim |
| author_facet | Jung-Min Kim Yeon-Suk Yang Jaehyoung Hong Sachin Chaugule Hyonho Chun Marjolein CH van der Meulen Ren Xu Matthew B Greenblatt Jae-hyuck Shim |
| author_sort | Jung-Min Kim |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T16:33:45Z |
| format | Article |
| id | doaj.art-435d9b2fd74c49e8a18463a57619a847 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:33:45Z |
| publishDate | 2022-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-435d9b2fd74c49e8a18463a57619a8472022-12-22T03:25:03ZengeLife Sciences Publications LtdeLife2050-084X2022-08-011110.7554/eLife.78069Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathwayJung-Min Kim0https://orcid.org/0000-0002-9072-4293Yeon-Suk Yang1Jaehyoung Hong2Sachin Chaugule3Hyonho Chun4Marjolein CH van der Meulen5https://orcid.org/0000-0001-6637-9808Ren Xu6https://orcid.org/0000-0001-6578-4553Matthew B Greenblatt7Jae-hyuck Shim8https://orcid.org/0000-0002-4947-3293Department of Medicine, University of Massachusetts Medical School, Worcester, United StatesDepartment of Medicine, University of Massachusetts Medical School, Worcester, United StatesDepartment of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaDepartment of Medicine, University of Massachusetts Medical School, Worcester, United StatesDepartment of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of KoreaMeinig School of Biomedical Engineering and Sibley School of Mechanical & Aerospace Engineering, Cornell University, Ithaca, United States; Research Division, Hospital for Special Surgery, New York, United StatesState Key Laboratory of Cellular Stress Biology, School of Medicine, Xiamen University, Fujian, China; Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaResearch Division, Hospital for Special Surgery, New York, United States; Department of Pathology and Laboratory Medicine, Weill Cornell, New York, United StatesDepartment of Medicine, University of Massachusetts Medical School, Worcester, United States; Horae Gene Therapy Center, Worcester, United States; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, Worcester, United StatesEmerging 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.https://elifesciences.org/articles/78069MEKERKmTORosteoblast |
| spellingShingle | Jung-Min Kim Yeon-Suk Yang Jaehyoung Hong Sachin Chaugule Hyonho Chun Marjolein CH van der Meulen Ren Xu Matthew B Greenblatt Jae-hyuck Shim Biphasic regulation of osteoblast development via the ERK MAPK–mTOR pathway eLife MEK ERK mTOR osteoblast |
| 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 | MEK ERK mTOR osteoblast |
| url | https://elifesciences.org/articles/78069 |
| work_keys_str_mv | AT jungminkim biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway AT yeonsukyang biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway AT jaehyounghong biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway AT sachinchaugule biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway AT hyonhochun biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway AT marjoleinchvandermeulen biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway AT renxu biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway AT matthewbgreenblatt biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway AT jaehyuckshim biphasicregulationofosteoblastdevelopmentviatheerkmapkmtorpathway |