Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model

Nasu, Y.; Nishida, Keiichiro; Miyazawa, Shinichi; Komiyama, Takamitsu; Kadota, Yasutaka; Abe, Nobuhiro; Yoshida, Aki; Hirohata, Satoshi; Ohtsuka, Aiji; Ozaki, Toshifumi

doi:10.1016/j.joca.2007.10.014

Cited by 133 publications

(89 citation statements)

References 27 publications

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“…In contrast, comprehensive evidence from experiments with isolated lungs and those with intact animals suggest that on the protein level the overall effect of TSA in vivo tends to be anti-inflammatory. This conclusion is corroborated by the antiinflammatory action of HDACi in experimental models of acute lung injury (this study), asthma [20], sepsis [21], arthritis [22,38], autoimmune encephalomyelitis [39], colitis [40] and concanavalin-A-induced hepatitis [21]. From the present study we suggest that the discrepancies between the in vivo and perfused lung studies on the one hand, and the cell culture studies on the other may be ascribed to the focus on M A N U S C R I P T has not revealed a pattern that correlated with the current findings (data not shown).…”

Section: Discussionsupporting

confidence: 73%

Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

Dombrowsky

Barrenschee

Kunze

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Histone deacetylase (HDAC) isoenzymes have been suggested as possible drug targets in pulmonary cancer and in inflammatory lung diseases such as asthma and COPD. Whether HDAC inhibition is pro-or anti-inflammatory is under debate.To further examine this clinically relevant paradigm, we analyzed 8 genes that are upregulated by two pro-inflammatory stimuli, i.e. endotoxin and mechanical stress (overventilation), in isolated rat and mouse lungs, respectively. We studied the effect of the HDAC inhibitor trichostatin A (TSA) under control conditions, in response to endotoxin and overventilation, and on the effects of the steroid dexamethasone.TSA affected gene expression largely independent of the stimulus (endotoxin, overventilation) and the species (rat, mouse) leading to upregulation of some genes (Tnf, Cxcl2) and downregulation of others (Cxcl10, Timp1, Selp, Il6). At the protein level, TSA reduced the stimulated release of TNF, MIP-2α and IL-6, indicating that TSA may affect protein translation independent from gene transcription. In general, the anti-inflammatory effects of TSA on gene expression and protein release were additive to that of dexamethasone, suggesting that both drugs employ different mechanisms.We conclude that pro-inflammatory stimuli induce distinct sets of genes that are regulated by HDAC in a diverse, but consistent manner across two rodent species.The present findings together with previous in vivo studies suggest that the effect of HDAC inhibition in the intact lung is in part anti-inflammatory.

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Section: Discussionsupporting

confidence: 73%

Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

Dombrowsky

Barrenschee

Kunze

et al. 2009

Pulmonary Pharmacology & Therapeutics

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“…30 Another HDACi, ITF2357, which inhibits class I and II HADCs, reduced the expression of proinflammatory cytokines in synovial tissues, but the mechanisms are not fully clear. 31,32 Therefore, it is plausible that the inhibition of HDACs may have a beneficial effect on the management of OA. Indeed, various studies have shown the protective effect of HDACi on cartilage degeneration using a collagen antibodyeinduced arthritis or destabilization of the medial meniscus mouse model of OA.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Makki

Haqqi

2016

The American Journal of Pathology

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Osteoarthritis (OA) is the most common whole-joint disease and is characterized by progressive loss of the cartilage matrix. Matrix metallopeptidase-13 (MMP-13) is a highly active and an abundantly expressed protease in OA cartilage and chondrocytes and degrades type II collagen and proteoglycans. We investigated the mechanism of MMP-13 suppression by histone deacetylase inhibitor vorinostat (SAHA). OA chondrocytes were obtained from knee cartilage after enzymatic digestion and treated with IL-1b in the absence or presence of various histone deacetylase inhibitors. Gene expression was quantified using quantitative RT-PCR. Protein expression and chromatin modifications were determined by Western immunoblotting using specific antibodies. The effect of IL-6 on the expression of MMP-13 was determined by treating chondrocytes with recombinant IL-6 or by IL6 knockdown using IL6-specific siRNA. We found that SAHA is a potent suppressor of IL-1beinduced MMP-13, tumor necrosis factor-a, and other catabolic marker expression in OA chondrocytes. Interestingly, SAHA rescued the COL2A1 and ACAN expression in OA chondrocytes that was down-regulated by IL-1b. Of importance is our finding that IL-6estimulated MMP-13 expression was independent of IL-1b stimulation and was blocked by SAHA, suggesting that SAHA inhibits IL-6 signaling in OA chondrocytes. Taken together, our results suggest that SAHA could be used as a therapeutic agent for the management of OA. (Am J Pathol 2016 http:// dx

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“…Our present findings support the hypothesis that the efficacy of HDACIs in models of acute and chronic inflammation, especially if characterized by a neutrophilic component, could be consequent to potentiation of AnxA1-mediated pro-resolution properties. 53 In conclusion, we report how integrative genome-wide computational approaches can be useful for the discovery of drug mechanisms of action. Our results add new knowledge to the complex anti-inflammatory mechanisms of action of HDACIs, showing that the mediator AnxA1 has non-redundant function especially for their pro-resolving effects, some of which described here for the first time (e.g., pro-phagocytic properties).…”

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confidence: 93%

Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors

2012

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Despite several therapies are currently available to treat inflammatory diseases, new drugs to treat chronic conditions with less side effects and lower production costs are still needed. An innovative approach to drug discovery, the Connectivity Map (CMap), shows how integrating genome-wide gene expression data of drugs and diseases can accelerate this process. Comparison of genome-wide gene expression data generated with Annexin A1 (AnxA1) with the CMap revealed significant alignment with gene profiles elicited by histone deacetylase inhibitors (HDACIs), what made us to hypothesize that AnxA1 might mediate the anti-inflammatory actions of HDACIs. Addition of HDACIs (valproic acid, sodium butyrate and thricostatin A) to mouse macrophages caused externalization of AnxA1 with concomitant inhibition of cytokine gene expression and release, events that occurred independently since this inhibition was retained in AnxA1 null macrophages. However, novel AnxA1-mediated functions for HDACIs could be unveiled, including promotion of neutrophil apoptosis and macrophage phagocytosis, both steps crucial for effective resolution of inflammation. In a model of acute resolving inflammation, administration of valproic acid and sodium butyrate to mice at the peak of disease accelerated resolution processes in wild type, but much more modestly in AnxA1 null mice. Deeper analyses revealed a role for endogenous AnxA1 in the induction of neutrophil death in vivo by HDACIs. In summary, interrogation of the CMap revealed an unexpected association between HDACIs and AnxA1 that translated in mechanistic findings with particular impact on the processes that regulate the resolution of inflammation. We propose non-genomic modulation of AnxA1 in immune cells as a novel mechanism of action for HDACIs, which may underlie their reported efficacy in models of chronic inflammatory pathologies.

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Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model

Abstract: The systemic administration of TSA ameliorated synovial inflammation in CAIA mice. Subsequently cartilage destruction was also suppressed by TSA, at least in part, by modulating chondrocyte gene expression.

Cited by 133 publications

References 27 publications

Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors

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