Kruppel-like factor 4 upregulates matrix metalloproteinase 13 expression in chondrocytes via mRNA stabilization.
Articular cartilage
Histone deacetylase
KLF4
Matrix metalloproteinase
Journal
Cell and tissue research
ISSN: 1432-0878
Titre abrégé: Cell Tissue Res
Pays: Germany
ID NLM: 0417625
Informations de publication
Date de publication:
Nov 2020
Nov 2020
Historique:
received:
31
05
2019
accepted:
29
04
2020
pubmed:
20
6
2020
medline:
15
7
2021
entrez:
20
6
2020
Statut:
ppublish
Résumé
Matrix metalloproteinase 13 (MMP13) is indispensable for normal skeletal development and is also a principal proteinase responsible for articular joint pathologies. MMP13 mRNA level needs to be tightly regulated in both positive and negative manners to achieve normal development and also to prevent joint destruction. We showed previously that Kruppel-like factor 4 (KLF4) strongly induces the expression of members of the MMP family of genes including that for MMP13 in cultured chondrocytes. Through expression-based screening of approximately 400 compounds, we identified several that efficiently downregulated MMP13 gene expression induced by KLF4. Compounds grouped as topoisomerase inhibitors (transcriptional inhibitors) downregulated MMP13 expression levels, which proved the validity of our screening method. In this screening, trichostatin A (TSA) was identified as one of the most potent repressors. Mechanistically, increased MMP13 mRNA levels induced by KLF4 were not mainly caused by increased rates of RNA polymerase II-mediated MMP13 transcription, but arose from escaping mRNA decay. TSA treatment almost completely blunted the effect of KLF4. Importantly, KLF4 was detected in chondrocytes at the joint destruction sites in a rodent model of osteoarthritis. Our results partially explain how KLF4 regulates numerous proteinase gene expressions simultaneously in chondrocytes. Also, these observations suggest that modulation of KLF4 activity or expression could be a novel therapeutic target for osteoarthritis.
Identifiants
pubmed: 32556726
doi: 10.1007/s00441-020-03228-3
pii: 10.1007/s00441-020-03228-3
doi:
Substances chimiques
Klf4 protein, mouse
0
Klf4 protein, rat
0
Kruppel-Like Factor 4
0
Kruppel-Like Transcription Factors
0
RNA, Messenger
0
Matrix Metalloproteinase 13
EC 3.4.24.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
307-319Subventions
Organisme : MEXT
ID : 17K11611
Organisme : MEXT
ID : 17K17322
Organisme : MEXT
ID : 17K11960
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