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Cited by 62Osteoarthritis Treatment and MechanismsMicroRNA in disease regulationBone Tumor Diagnosis and Treatments

MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway

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Papaioannou, Garyfallia, Mirzamohammadi, Fatemeh, Lisse, Thomas S, Nishimori, Shigeki, Wein, Marc N, Kobayashi, Tatsuya·2015·Journal of Bone and Mineral Research
DOI 10.1002/jbmr.2438PMC PMC5380142
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Abstract

Growth plate chondrocytes go through multiple differentiation steps and eventually become hypertrophic chondrocytes. The parathyroid hormone (PTH)-related peptide (PTHrP) signaling pathway plays a central role in regulation of hypertrophic differentiation, at least in part, through enhancing activity of histone deacetylase 4 (HDAC4), a negative regulator of MEF2 transcription factors that drive hypertrophy. We have previously shown that loss of the chondrocyte-specific microRNA (miRNA), miR-140, alters chondrocyte differentiation including mild acceleration of hypertrophic differentiation. Here, we provide evidence that miR-140 interacts with the PTHrP-HDAC4 pathway to control chondrocyte differentiation. Heterozygosity of PTHrP or HDAC4 substantially impaired animal growth in miR-140 deficiency, whereas these mutations had no effect in the presence of miR-140. miR-140–deficient chondrocytes showed increased MEF2C expression with normal levels of total and phosphorylated HDAC4, indicating that the miR-140 pathway merges with the PTHrP-HDAC4 pathway at the level of MEF2C. miR-140 negatively regulated p38 mitogen-activated protein kinase (MAPK) signaling, and inhibition of p38 MAPK signaling reduced MEF2C expression. These results demonstrate that miR-140 ensures the robustness of the PTHrP/HDAC4 regulatory system by suppressing MEF2C-inducing stimuli. © 2014 American Society for Bone and Mineral Research © 2015 American Society for Bone and Mineral Research

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Authors
Papaioannou, G., Mirzamohammadi, F., Lisse, T. S., Nishimori, S., Wein, M. N., & Kobayashi, T.
Affiliations
Harvard University (US)
Corresponding author
Wein, Marc N
ORCID
Venue
Journal of Bone and Mineral Research
Publisher
Oxford University Press (OUP)
Published
2014-12-22
Volume
30
Issue
6
Pages
1044-1052
ISSN
  • 0884-0431 (ISSN-L)
  • 1523-4681
DOI
10.1002/jbmr.2438
PMC
PMC5380142
OpenAlex
W2023115791
Cited by
62
References
2
Citations by year
2025: 2 · 2024: 10 · 2023: 1 · 2022: 5 · 2021: 3 · 2020: 9 · 2019: 9 · 2018: 4 · 2017: 5 · 2016: 3 · 2015: 10 · 2014: 1
FWCI
5.25
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Journal of Bone and Mineral Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health
  • Harvard Stem Cell Institute (SG-0090-13)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR054500, R01AR056645, P30AR066261, AR054500, AR056645)
Topics
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
Keywords
miR-140, parathyroid hormone-related protein, HDAC4, MEF2C, chondrocyte hypertrophy, growth plate chondrocytes, p38 MAPK signaling, microRNA regulation, chondrogenesis, skeletal development
MeSH terms
Animals, Histone Deacetylases, Hypertrophy, Signal Transduction, Mice, Knockout, Chondrocytes, MicroRNAs, Parathyroid Hormone-Related Protein, Mice, MEF2 Transcription Factors

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