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Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis

Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify...

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Autores principales: Kawata, Manabu, McClatchy, Daniel B., Diedrich, Jolene K., Olmer, Merissa, Johnson, Kristen A., Yates, John R., Lotz, Martin K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544226/
https://www.ncbi.nlm.nih.gov/pubmed/37681413
http://dx.doi.org/10.1172/jci.insight.170513
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author Kawata, Manabu
McClatchy, Daniel B.
Diedrich, Jolene K.
Olmer, Merissa
Johnson, Kristen A.
Yates, John R.
Lotz, Martin K.
author_facet Kawata, Manabu
McClatchy, Daniel B.
Diedrich, Jolene K.
Olmer, Merissa
Johnson, Kristen A.
Yates, John R.
Lotz, Martin K.
author_sort Kawata, Manabu
collection PubMed
description Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat — a class I selective histone deacetylase (HDAC) inhibitor — had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.
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spelling pubmed-105442262023-10-03 Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis Kawata, Manabu McClatchy, Daniel B. Diedrich, Jolene K. Olmer, Merissa Johnson, Kristen A. Yates, John R. Lotz, Martin K. JCI Insight Research Article Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat — a class I selective histone deacetylase (HDAC) inhibitor — had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD. American Society for Clinical Investigation 2023-09-08 /pmc/articles/PMC10544226/ /pubmed/37681413 http://dx.doi.org/10.1172/jci.insight.170513 Text en © 2023 Kawata et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Kawata, Manabu
McClatchy, Daniel B.
Diedrich, Jolene K.
Olmer, Merissa
Johnson, Kristen A.
Yates, John R.
Lotz, Martin K.
Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis
title Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis
title_full Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis
title_fullStr Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis
title_full_unstemmed Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis
title_short Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis
title_sort mocetinostat activates krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544226/
https://www.ncbi.nlm.nih.gov/pubmed/37681413
http://dx.doi.org/10.1172/jci.insight.170513
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