Anglia Ruskin University, Faculty of Medical Science, Chelmsford, United Kingdom.
Cranfield University, Bedfordshire, United Kingdom.
J Sex Med. 2018 Jul;15(7):947-957. doi: 10.1016/j.jsxm.2018.05.003. Epub 2018 Jun 8.
Peyronie's disease (PD) is a chronic fibrotic disease of the penis affecting a significant number of men worldwide without effective medical treatments. Myofibroblasts are pivotal in the pathogenesis of PD. Adenosine and adenosine receptors have been suggested to be involved in the pathophysiology of fibrosis.
To understand the role of adenosine receptors in myofibroblast transformation in PD.
Fibroblasts were isolated from the non-PD tunica albuginea (TA) tissue and PD plaque tissue and were transformed into myofibroblasts using transforming growth factor (TGF)-β1. Quantification of α-smooth muscle actin and adenosine receptors (adenosine receptor A1 [ADORA1], adenosine receptor A2A, adenosine receptor A2B [ADORA2B], and adenosine receptor A3) was performed using immuno-cytochemistry, in-cell enzyme-linked immuno-sorbent assay (ICE), and real-time reverse transcription quantitative polymerase chain reaction. The effect of various adenosine receptor agonists or antagonists on TGF-β1-induced myofibroblast transformation was measured using ICE.
Expression of adenosine receptors in myofibroblasts obtained from human TA and the effect of adenosine receptor ligands on myofibroblast transformation were investigated.
The experiments showed that the protein and messenger RNA levels of α-smooth muscle actin in non-PD TA cells and PD plaque-derived cells were significantly higher in cells exposed to TGF-β1 than those not treated with TGF-β1. 2 of 4 adenosine receptors (ADORA1 and ADORA2B) were found to be expressed in both cell populations. Among various adenosine receptor agonists/antagonist investigated, only ADORA2B agonist, BAY 60-6583, significantly inhibited myofibroblast transformation in a concentration-dependent manner when applied simultaneously with TGF-β1 (IC = 30 μmol/L).
ADORA2B agonists may be clinically efficacious in early-stage PD. STRENGTHS & LIMITATIONS: The strength of this study is the use of primary fibroblasts from human TA. Limitation of the study is the high concentrations of the ligands used.
The effect of an ADORA2B agonist on TGF-β1-induced myofibroblast transformation shows a novel potential therapeutic target for PD if applied during early, non-stable phase of PD. Mateus M, Ilg MM, Stebbeds WJ, et al. Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2018;15:947-957.
佩罗尼氏病（PD）是一种影响全球大量男性的阴茎慢性纤维化疾病，目前尚无有效的医学治疗方法。肌成纤维细胞在 PD 的发病机制中起着关键作用。腺苷和腺苷受体被认为参与了纤维化的病理生理过程。
了解腺苷受体在 PD 中的肌成纤维细胞转化中的作用。
从非 PD 白膜组织和 PD 斑块组织中分离出成纤维细胞，并通过转化生长因子（TGF）-β1 将其转化为肌成纤维细胞。使用免疫细胞化学、细胞内酶联免疫吸附试验（ICE）和实时逆转录定量聚合酶链反应（PCR）定量检测α-平滑肌肌动蛋白和腺苷受体（腺苷受体 A1[ADORA1]、腺苷受体 A2A、腺苷受体 A2B[ADORA2B]和腺苷受体 A3）的表达。使用 ICE 测量各种腺苷受体激动剂或拮抗剂对 TGF-β1 诱导的肌成纤维细胞转化的影响。
实验表明，与未用 TGF-β1 处理的细胞相比，暴露于 TGF-β1 的非 PD TA 细胞和 PD 斑块衍生细胞中的α-平滑肌肌动蛋白蛋白和信使 RNA 水平明显升高。在这两种细胞群中均发现了 4 种腺苷受体中的 2 种（ADORA1 和 ADORA2B）表达。在所研究的各种腺苷受体激动剂/拮抗剂中，只有 ADORA2B 激动剂 BAY 60-6583 在与 TGF-β1 同时应用时以浓度依赖性方式显著抑制肌成纤维细胞转化（IC=30μmol/L）。
ADORA2B 激动剂在早期 PD 中可能具有临床疗效。
本研究的优势在于使用了来自人 TA 的原代成纤维细胞。研究的局限性在于配体的高浓度。
ADORA2B 激动剂对 TGF-β1 诱导的肌成纤维细胞转化的影响为 PD 提供了一个新的潜在治疗靶点，如果在 PD 的早期、非稳定阶段应用，可能具有治疗作用。
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