Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Hemmatazad, Hossein; Rodrigues, Hanna Maciejewska; Maurer, Britta; Brentano, Fabia; Pileckytė, Margarita; Distler, Jörg H W; Gay, Renate E.; Michel, Beat A.; Gay, Steffen; Huber, Lars C; Distler, Oliver; Jüngel, Astrid

doi:10.1002/art.24494

Cited by 98 publications

(63 citation statements)

References 37 publications

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“…Bar indicates 100 mm. Fibroblasts were transfected with scramble siRNA or siRNA specific to HDAC2 by using Lipofectamine reagent for 48 h and were then treated with TGF-b1 (10 ng ml 21 ) for 24 h. Results were similar from four independent experiments. DAPI, 4,6-diamidino-2-phenylindole; HDAC2, histone deacetylase 2; PAI-1, plasminogen activator inhibitor-1; PD, Peyronie's disease; siRNA, small interfering RNA; TGF-b1, transforming growth factor-b1.…”

Section: Resultsmentioning

confidence: 86%

“…16 Recent studies have also reported epigenetic modifications in gene transcription in systemic sclerosis, 19,20 a disease characterized by severe fibrosis of the skin and various internal organs, and silencing of HDAC7 decreased the production of collagen I and collagen III. 21 These findings suggest an importance of epigenetic modification in the pathogenesis of fibrotic diseases and, furthermore, that therapies aimed at blocking individual HDAC isoforms might be efficacious for these conditions. In the present study, the cytokine (TGF-b1)-induced expression of HDAC2 was significantly increased in the PD fibroblasts.…”

Section: Discussionmentioning

confidence: 98%

“…8 Briefly, the plaque tissue was transferred into sterile vials containing Hank's balanced salt solution (Gibco, Carlsbad, CA, USA) and was washed three times in phosphate-buffered saline. Biopsy tissue was minced into 1-mm 2 segments and incubated in a shaker in 12.5 ml Dulbecco's modified Eagle medium supplemented with 0.06% collagenase A (Sigma-Aldrich, St Louis, MO, USA) for 1 h. The cells and tissue fragments were collected by centrifugation (400 g35 min), washed in fresh culture medium, and placed in 100-mm cell culture dishes (Falcon-Becton Dickinson Labware, Franklin Lakes, NJ, USA) under standard cell culture conditions with Dulbecco's modified Eagle medium supplemented with 10% fetal calf serum, penicillin (100 U ml 21 ) and streptomycin (100 mg ml 21 ). The dishes were incubated in a humidified 37 uC incubator with 5% CO 2 .…”

Section: Primary Fibroblast Culturementioning

confidence: 99%

“…By contrast, silencing of HDAC7 demonstrated an anti-fibrotic effect without influencing the expression of these profibrotic molecules in fibroblasts isolated from patients with systemic sclerosis. 21 Therefore, inhibition of individual HDAC isoforms by use of RNA interference technology may have advantages in the development of more specific and less toxic epigenetic therapies for PD. Further studies are needed to determine the therapeutic role of HDAC2 knockdown in PD models in vivo.…”

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confidence: 99%

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Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Ryu¹,

Kim²,

Choi³

et al. 2013

Asian J Androl

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Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-b1 (TGF-b1). Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle a-actin and extracellular matrix proteins, including plasminogen activator inhibitor-1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-b1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-b1-induced extracellular matrix production by blocking TGF-b1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-b1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD.

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Section: Resultsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 98%

Section: Primary Fibroblast Culturementioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Ryu¹,

Kim²,

Choi³

et al. 2013

Asian J Androl

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“…Total RNA was isolated and converted into cDNA and gene expression was quantified by Real-time PCR as described (20,21).…”

Section: Rna Extractionmentioning

confidence: 99%

Epigenetics and rheumatoid arthritis: The role of SENP1 in the regulation of MMP-1 expression

Maciejewska-Rodrigues¹,

Karouzakis²,

Strietholt³

et al. 2010

Journal of Autoimmunity

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The aggressive phenotype of RA synovial fibroblasts (RASF) is characterised by the increased expression of matrix metalloproteinase (MMP)-1 as well as the small ubiquitin like modifier (SUMO)-1 and decreased expression of SUMO-specific protease SENP1. Since we showed an increased activity of acetyltransferases in this autoimmune disease, we wanted to analyse whether this affects the expression of MMP-1 and can be reversed by the reconstitution of SENP1.In RASF, the acetylation of histone H4 was significantly increased in the distal region of the MMP-1 promoter by 274 ± 36% compared to OASF. Most interestingly, overexpression of SENP1 in RASF decreased acetylation specifically in this region by 51 ± 0.5% and globally by 73 ± 11%. Furthermore, the overexpression of SENP1 resulted in a downregulation of MMP-1 at both the mRNA (58  7%) and protein levels (28 ± 6%), significantly reduced the invasiveness of RASF (from 34  9% to 2  2%) and led to an accumulation of histone deacetylase 4 (HDAC4) on the MMP-1 promoter (197 ± 36%). Interestingly, SENP1 failed to modulate the expression of MMP-1 in the cells silenced for HDAC4. This is the first study linking the SUMOylation pathway and the production of MMP-1 to an epigenetic control mechanism mediated through histone acetylation which has a functional consequence for the invasiveness of RASF.

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MicroRNA‐29, a key regulator of collagen expression in systemic sclerosis

Maurer

Stańczyk

Jüngel

et al. 2010

Arthritis & Rheumatism

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369

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Objective. To investigate the role of microRNA (miRNA) as posttranscriptional regulators of profibrotic genes in systemic sclerosis (SSc).Methods. MicroRNA, which target collagens, were identified by in silico analysis. Expression of miRNA-29 (miR-29) was determined by TaqMan real-time polymerase chain reaction analysis of skin biopsy and fibroblast samples from SSc patients and healthy controls as well as in the mouse model of bleomycininduced skin fibrosis. Cells were transfected with precursor miRNA (pre-miRNA)/anti-miRNA of miR-29 using Lipofectamine. Collagen gene expression was also studied in luciferase reporter gene assays. For stimulation, recombinant transforming growth factor ␤ (TGF␤), platelet-derived growth factor B (PDGF-B), or interleukin-4 (IL-4) was used. The effects of inhibiting PDGF-B and TGF␤ signaling on the levels of miR-29 were studied in vitro and in the bleomycin model.Results. We found that miR-29a was strongly down-regulated in SSc fibroblasts and skin sections as compared with the healthy controls. Overexpression in SSc fibroblasts significantly decreased, and accordingly, knockdown in normal fibroblasts increased, the levels of messenger RNA and protein for type I and type III collagen. In the reporter gene assay, cotransfection with pre-miR-29a significantly decreased the relative luciferase activity, which suggests a direct regulation of collagen by miR-29a. TGF␤, PDGF-B, or IL-4 reduced the levels of miR-29a in normal fibroblasts to those seen in SSc fibroblasts. Similar to human SSc, the expression of miR-29a was reduced in the bleomycin model of skin fibrosis. Inhibition of PDGF-B and TGF␤ pathways by treatment with imatinib restored the levels of miR-29a in vitro and in the bleomycin model in vivo.Conclusion. These data add the posttranscriptional regulation of collagens by miR-29a as a novel aspect to the fibrogenesis of SSc and suggest miR-29a as a potential therapeutic target.

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Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

Cited by 98 publications

References 37 publications

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

Epigenetics and rheumatoid arthritis: The role of SENP1 in the regulation of MMP-1 expression

MicroRNA‐29, a key regulator of collagen expression in systemic sclerosis

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