Description
Kruppel-like factor-4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissue cells. To explore novel therapeutic candidates for osteoarthritis (OA), high-throughput screening (HTS) with 11,948 compounds was per-formed using a reporter cell line detecting endogenous KLF4 activation. Eighteen com-pounds were identified through the HTS and confirmed in a secondary screen. Among them, mocetinostat, a class I histone deacetylase inhibitor, had the best biological activi-ties. Mocetinostat upregulated chondrogenic genes in human chondrocytes, meniscal cells, and mesenchymal stem cells, while it down-regulated hypertrophic, inflammatory and cat-abolic genes in those cells and synoviocytes. Intraperitoneal administration of mocetino-stat into mice reduced severity of OA-associated changes in cartilage, meniscus and syno-vium and improved pain behaviors. Global gene expression and proteomics analyses re-vealed that regenerative and protective effects of mocetinostat depended on peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These findings qualify mocetino-stat as a potential candidate for disease modifying OA drugs.
[doi:10.25345/C5WH2DQ6S]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: KLF4 ; osteoarthritis
Contact
Principal Investigators:
(in alphabetical order)
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Martin K Lotz, MD, Scripps Research, USA
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dmcclat
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Number of distinct conditions across all analyses (original submission and reanalyses)
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Distinct condition labels are counted across all files submitted in the "Metadata" category
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Number of distinct biological replicates across all analyses (original submission and reanalyses)
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"N/A" means no results of this type were submitted.
Originally identified proteins that were automatically
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SwissProt
human reference database.
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Number of distinct protein accessions reported across all analyses (original submission and
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Number of distinct unmodified peptide sequences reported across all analyses (original
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Number of distinct peptide sequences (including modified variants or peptidoforms) reported
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Total number of peptide-spectrum matches (i.e. spectrum identifications) reported across all
analyses (original submission and reanalyses) associated with this dataset.
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Number of distinct proteins quantified across all analyses (original submission and reanalyses)
associated with this dataset.
Distinct protein accessions are counted across all files submitted in the "Statistical Analysis
of Quantified Analytes" category having a "Protein" column in this dataset.
"N/A" means no results of this type were submitted.
Number of distinct proteins found to be differentially abundant in at least one comparison
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A protein is differentially abundant if its change in abundance across conditions is found
to be statistically significant with an adjusted p-value <= 0.05 and lists no issues associated
with statistical tests for differential abundance.
Distinct protein accessions are counted across all files submitted in the "Statistical Analysis
of Quantified Analytes" category having a "Protein" column in this dataset.
"N/A" means no results of this type were submitted.
This dataset may not contain all raw spectra data as originally deposited in PRIDE.
It has been imported to MassIVE for reanalysis purposes, so its spectra data here may
consist solely of processed peak lists suitable for reanalysis with most software.