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Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis

INTRODUCTION: Osteoarthritis (OA) is a common joint disease that can cause gradual disability among the aging population. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor that regulates the expression of phase II antioxidant enzymes that provide protection against oxi...

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Autores principales: Cai, Dawei, Yin, Shasha, Yang, Jun, Jiang, Qing, Cao, Wangsen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583998/
https://www.ncbi.nlm.nih.gov/pubmed/26408027
http://dx.doi.org/10.1186/s13075-015-0774-3
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author Cai, Dawei
Yin, Shasha
Yang, Jun
Jiang, Qing
Cao, Wangsen
author_facet Cai, Dawei
Yin, Shasha
Yang, Jun
Jiang, Qing
Cao, Wangsen
author_sort Cai, Dawei
collection PubMed
description INTRODUCTION: Osteoarthritis (OA) is a common joint disease that can cause gradual disability among the aging population. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor that regulates the expression of phase II antioxidant enzymes that provide protection against oxidative stress and tissue damage. The use of histone deacetylase inhibitors (HDACi) has emerged as a potential therapeutic strategy for various diseases. They have displayed chondroprotective effects in various animal models of arthritis. Previous studies have established that Nrf2 acetylation enhances Nrf2 functions. Here we explore the role of Nrf2 in the development of OA and the involvement of Nrf2 acetylation in HDACi protection of OA. METHODS: Two OA models—monosodium iodoacetate (MIA) articular injection and destabilization of the medial meniscus (DMM)—were used with wild-type (WT) and Nrf2-knockout (Nrf2-KO) mice to demonstrate the role of Nrf2 in OA progression. A pan-HDACi, trichostatin A (TSA), was administered to examine the effectiveness of HDACi on protection from cartilage damage. The histological sections were scored. The expression of OA-associated matrix metalloproteinases (MMPs) 1, 3, and 13 and proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were assayed. The effectiveness of HDACi on OA protection was compared between WT and Nrf2-KO mice. RESULTS: Nrf2-KO mice displayed more severe cartilage damage in both the MIA and DMM models. TSA promoted the induction of Nrf2 downstream proteins in SW1353 chondrosarcoma cells and in mouse joint tissues. TSA also reduced the expression of OA-associated proteins MMP1, MMP3, and MMP13 and proinflammatory cytokines TNF-α, IL-1β, and IL-6. TSA markedly reduced the cartilage damage in both OA models but offered no significant protection in Nrf2-KO mice. CONCLUSIONS: Nrf2 has a major chondroprotective role in progression of OA and is a critical molecule in HDACi-mediated OA protection.
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spelling pubmed-45839982015-09-28 Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis Cai, Dawei Yin, Shasha Yang, Jun Jiang, Qing Cao, Wangsen Arthritis Res Ther Research Article INTRODUCTION: Osteoarthritis (OA) is a common joint disease that can cause gradual disability among the aging population. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor that regulates the expression of phase II antioxidant enzymes that provide protection against oxidative stress and tissue damage. The use of histone deacetylase inhibitors (HDACi) has emerged as a potential therapeutic strategy for various diseases. They have displayed chondroprotective effects in various animal models of arthritis. Previous studies have established that Nrf2 acetylation enhances Nrf2 functions. Here we explore the role of Nrf2 in the development of OA and the involvement of Nrf2 acetylation in HDACi protection of OA. METHODS: Two OA models—monosodium iodoacetate (MIA) articular injection and destabilization of the medial meniscus (DMM)—were used with wild-type (WT) and Nrf2-knockout (Nrf2-KO) mice to demonstrate the role of Nrf2 in OA progression. A pan-HDACi, trichostatin A (TSA), was administered to examine the effectiveness of HDACi on protection from cartilage damage. The histological sections were scored. The expression of OA-associated matrix metalloproteinases (MMPs) 1, 3, and 13 and proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were assayed. The effectiveness of HDACi on OA protection was compared between WT and Nrf2-KO mice. RESULTS: Nrf2-KO mice displayed more severe cartilage damage in both the MIA and DMM models. TSA promoted the induction of Nrf2 downstream proteins in SW1353 chondrosarcoma cells and in mouse joint tissues. TSA also reduced the expression of OA-associated proteins MMP1, MMP3, and MMP13 and proinflammatory cytokines TNF-α, IL-1β, and IL-6. TSA markedly reduced the cartilage damage in both OA models but offered no significant protection in Nrf2-KO mice. CONCLUSIONS: Nrf2 has a major chondroprotective role in progression of OA and is a critical molecule in HDACi-mediated OA protection. BioMed Central 2015-09-26 2015 /pmc/articles/PMC4583998/ /pubmed/26408027 http://dx.doi.org/10.1186/s13075-015-0774-3 Text en © Cai et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Cai, Dawei
Yin, Shasha
Yang, Jun
Jiang, Qing
Cao, Wangsen
Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis
title Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis
title_full Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis
title_fullStr Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis
title_full_unstemmed Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis
title_short Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis
title_sort histone deacetylase inhibition activates nrf2 and protects against osteoarthritis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583998/
https://www.ncbi.nlm.nih.gov/pubmed/26408027
http://dx.doi.org/10.1186/s13075-015-0774-3
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