Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine‐Induced Cartilage Degradation

Culley, K.L.; Wang, Hui; Barter, M.J.; Davidson, Rose; Swingler, T.E.; Destrument, Auriane; Scott, Jenny L.; Donell, Simon T.; Fenwick, Steve; Rowan, Andrew D.; Young, David A.; Clark, Ian M.

doi:10.1002/art.37965

Cited by 75 publications

(86 citation statements)

References 39 publications

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“…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. 30,31 To our knowledge, all of the reported HDACi have been shown to down-regulate catabolic gene expression in chondrocytes but are not able to alter anabolic gene expression, especially the expression of COL2A1 and ACAN. In this study, we found that SAHA could potentially restore the chondrocyte anabolic gene expression by downregulating the inflammatory cytokine and MMP expression and up-regulating the expression of anabolic markers COL2A1 and ACAN under pathologic conditions.…”

Section: Discussionmentioning

confidence: 98%

“…29 Treatment with TSA, valproic acid, or MS-275 blocks the cytokine-induced expression of MMP-1 and -13 in human articular chondrocytes. 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.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 98%

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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“…The primary human chondrocytes were isolated from articular cartilage of OA patients undergoing total knee replacement surgery as previously described [16]. Briefly, harvested cartilage was minced into small pieces and incubated in a trypsin-containing solution for 2 h at 37°C.…”

Section: Isolation and Culture Of Chondrocytesmentioning

confidence: 99%

Poly(ADP-ribose) polymerase 1 inhibition prevents interleukin-1β-induced inflammation in human osteoarthritic chondrocytes

Sun¹,

Zhou²,

Lv³

et al. 2015

ABBS

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Osteoarthritis (OA) is an age-related joint disease that is characterized by the degeneration of articular chondrocytes. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with inflammation response. We investigated the role of PARP-1 in interleukin-1β (IL-1β)-stimulated human articular chondrocytes and its underlying mechanism. Cell viability and apoptosis were evaluated by using 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide assay and flow cytometry, respectively. Tumor necrosis factor-α (TNF-α) level was measured by enzyme-linked immunosorbent assay. The mRNA and protein expression levels of PARP-1, IL-1 receptor (IL-1R), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined by real-time reverse transcriptase-polymerase chain reaction and western blot analysis, respectively. The expression and phosphorylation of NF-кB p65 were measured by western blot analysis. Results showed that stimulation of chondrocytes with IL-1β caused a significant up-regulation of PARP-1 and IL-1R, resulting in NF-кB p65 nuclear translocation and phosphorylation associated with an increase of TNF-α secretion and iNOS expression. PARP-1 was inhibited by siRNA transfection. Results showed that PARP-1 inhibition suppressed IL-1β-induced reduction of cell viability and up-regulation of cell apoptosis, with a reduced IL-1R expression. PARP-1 inhibition also effectively reversed IL-1β-induced inflammatory response through inhibiting the IL-1R/NF-кB pathway. These data suggested that PARP-1 inhibition prevents IL-1β-induced inflammation response at least partly by inhibiting the IL-1R/NF-кB signaling pathway in human articular chondrocytes. Moreover, PARP-1 inhibition reduced MMPs expression and increased TIMP-1 expression, suggesting that PARP-1 inhibition could suppress cartilage destruction by modulating the balance between MMPs and TIMP-1. Inhibition of PARP-1 might be useful in the treatment of OA.

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“…Moreover, HDACs, HDAC-1, -2, -3, and -7, regulate Mmp13 expression. Inhibition of these HDACs protects the cartilage destruction induced by IL-1 (interleukin-1), suggesting the potential therapeutic use of HDAC inhibitors for cytokine-induced cartilage degradation observed in OA [56,57].…”

Section: Histone Acetylationmentioning

confidence: 98%

Epigenetic regulation of chondrocyte differentiation

Hata

2015

Japanese Dental Science Review

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Chondrocytes play an essential role in endochondral bone development, which is requisite for mammalian skeletal development. During endochondral bone development, chondrocytes undergo well-organized stages of sequential differentiation, including proliferation and hypertrophy, a process harmoniously modulated by various transcription factors. Epigenetics, including DNA methylation and histone modification, has recently emerged as an essential regulatory system for gene expression, not only in physiological conditions, but also in human disease. During chondrocyte differentiation, transcriptional co-regulators, which form transcriptional protein complexes with specific transcription factors, are predominantly involved in this epigenetic process and cooperatively regulate chondrocyte gene expression. Importantly, several studies indicate that epigenetic regulators correlate with cartilage-related diseases, such as osteoarthritis, and are noted as a potential therapeutic target. Here, current studies of epigenetic regulation of chondrocyte differentiation are reviewed and novel aspects for the molecular mechanisms involved in chondrogenesis are introduced.

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Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine‐Induced Cartilage Degradation

Cited by 75 publications

References 39 publications

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

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

Poly(ADP-ribose) polymerase 1 inhibition prevents interleukin-1β-induced inflammation in human osteoarthritic chondrocytes

Epigenetic regulation of chondrocyte differentiation

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Class I Histone Deacetylase Inhibition Modulates Metalloproteinase Expression and Blocks Cytokine‐Induced Cartilage Degradation

Cited by 75 publications

References 39 publications

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

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

Poly(ADP-ribose) polymerase 1 inhibition prevents interleukin-1&beta;-induced inflammation in human osteoarthritic chondrocytes

Epigenetic regulation of chondrocyte differentiation

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Poly(ADP-ribose) polymerase 1 inhibition prevents interleukin-1β-induced inflammation in human osteoarthritic chondrocytes