transforming growth factor-β

Article of the Week: Silencing histone deacetylase 2 induces regression of fibrotic plaque in Peyronie’s disease

December 10, 2014/by admin Z.9

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Professor Ji-Kan Ryu discussing his paper.

If you only have time to read one article this week, it should be this one.

Silencing histone deacetylase 2 using small hairpin RNA induces regression of fibrotic plaque in a rat model of Peyronie’s disease

Ki-Dong Kwon, Min Ji Choi, Jin-Mi Park, Kang-Moon Song, Mi-Hye Kwon, Dulguun Batbold, Guo Nan Yin, Woo Jean Kim, Ji-Kan Ryu and Jun-Kyu Suh

National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea

Read the full article

OBJECTIVES

To examine the therapeutic effect of adenovirus encoding histone deacetylase 2 (HDAC2) small hairpin RNA (Ad-HDAC2 shRNA) in a rat model of Peyronie’s disease (PD) and to determine the mechanisms by which HDAC2 knockdown ameliorates fibrotic responses in primary fibroblasts derived from human PD plaque.

MATERIAL AND METHODS

Rats were distributed into four groups (n = 6 per group): age-matched controls without treatment; rats in which PD has been induced (PD rats) without treatment; PD rats receiving a single injection of control adenovirus encoding scrambled small hairpin RNA (Ad-shRNA) (day 15; 1 × 10⁸ pfu/0.1 mL phosphate-buffered saline [PBS]); and PD rats receiving a single injection of Ad-HDAC2 shRNA (day 15; 1 × 10⁸ pfu/0.1 mL PBS) into the lesion. PD-like plaque was induced by repeated intratunical injections of 100 μL each of human fibrin and thrombin solutions on days 0 and 5. On day 30, the penis was harvested for histological examination. Fibroblasts isolated from human PD plaque were pretreated with HDAC2 small interfering (si)RNA (100 pmoL) and then stimulated with transforming growth factor (TGF)-β1 (10 ng/mL) to determine hydroxyproline levels, procollagen mRNA, apoptosis and protein expression of poly(ADP-ribose) polymerase 1 (PARP1) and cyclin D1.

RESULTS

We observed that Ad-HDAC2 shRNA decreased inflammatory cell infiltration, reduced transnuclear expression of phospho-Smad3 and regressed fibrotic plaque of the tunica albuginea in PD rats in vivo. siRNA-mediated silencing of HDAC2 significantly decreased the TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts and collagen production, and induced apoptosis by downregulating the expression of PARP1, and decreased the expression of cyclin D1 (a positive cell-cycle regulator) in primary cultured fibroblasts derived from human PD plaque in vitro.

CONCLUSION

Specific inhibition of HDAC2 with RNA interference may represent a novel targeted therapy for PD.

Editorial: Histone deacetylase inhibition: a new target for Peyronie’s disease?

December 10, 2014/by Selim Cellek

Peyronie’s disease is a chronic and progressive disease characterised by fibrotic plaque of the tunica albuginea of the penis that can cause deformity, pain during erection and erectile dysfunction. Fibrosis is the hallmark of the pathology of Peyronie’s disease and is known to be driven by fibroblasts and myofibroblasts, which produce excessive amounts of extracellular matrix proteins and, hence, disturb the architecture of the tunica albuginea.

In this issue of BJUI, Kwon et al. [1] have shown that selective inhibition of histone deacetylase isoform 2 (HDAC-2) using a small hairpin silencing RNA elicits reversal of plaque development in vivo and prevention of collagen production and myofibroblast transformation in vitro. Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from lysine amino acid in histones, causing histones to wrap around the DNA tightly and, ultimately, affecting gene transcription. In addition HDACs can de-acetylate cytosolic proteins and hence alter their function. Because of their direct effect on cell growth and death, HDACs have recently been attractive targets for anti-cancer drug development. Currently, there are > 100 clinical trials recruiting patients to investigate the clinical efficacy of HDAC inhibitors, most of which are non-selective HDAC inhibitors, bearing in mind that there are 11 isoforms of HDACs.

HDAC inhibitors have been suggested to have anti-fibrotic effects in the lung, liver, kidney and skin. They have been shown to reduce myofibroblast transformation and fibroblast activation, and counteract TGF-β actions and extracellular matrix production [2]. Although the exact mode of action of HDAC inhibitors in fibrosis is not clear, it has been suggested that HDAC inhibitors might repress the TGF-β pathway and interfere with phosphorylation and activation of STAT3, a key transcription factor in inflammatory pathways. Among all the isoforms of HDAC, HDAC-2 has been implicated in pathogenesis of fibrosis, firstly in kidney fibrosis [3] and later in Peyronie’s disease [4]. Currently available small-molecule HDAC inhibitors target more than one isoform of HDAC; to our knowledge isoform-selective small-molecule inhibitors are not available yet. Kwon et al. [1] have solved this problem using small hairpin silencing RNA to target HDAC-2 specifically. Although the clinical feasibility of such a silencing RNA approach remains to be tested, their study nevertheless gives an important indication for HDAC-2 as a possible target for fibrotic diseases, such as Peyronie’s. No doubt further research and development will be required to validate this target and develop small-molecule inhibitors selective for HDAC-2.

Read the full article

Selim Cellek* and David J. Ralph*†

*Centre for Biomedical Engineering, Cranfield University, Cranfield, and † University College London Hospital, London, UK

References

1 Kwon K-D, Choi MJ, Park J-M et al. Silencing histone deacetylase 2 using small hairpin RNA induces regression of fibrotic plaque in a rat model of Peyronie’s disease. BJU Int 2014; 114: 926–36

2 Pang M, Zhuang S. Histone deacetylase: a potential therapeutic target for fibrotic disorders. J Pharmacol Exp Ther 2010; 335: 266–72

3 Noh H, Oh EY, Seo JY et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am J Physiol Renal Physiol 2009; 297: F729–39

4 Ryu JK, Kim WJ, Choi MJ et al. Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie’s plaque. Asian J Androl 2013; 15: 640–5

Video: Inducing regression of fibrotic plaque in Peyronie’s disease by silencing histone deacetylase 2

December 10, 2014/by admin Z.9