帕立骨化醇抑制Wnt/β-连环蛋白信号通路并改善博来霉素诱导的硬皮病模型中的皮肤纤维化。

Paricalcitol Inhibits Wnt/β-Catenin Signaling Pathway and Ameliorates Dermal Fibrosis in Bleomycin Induced Scleroderma Model.

作者信息

Gözel Nevzat, Duran Fikret, Yildirim Ahmet, Yolbaş Servet, Önalan Ebru, Özercan İbrahim Hanifi, Koca Süleyman Serdar

机构信息

Department of Internal Medicine, Medical Faculty of Fırat University, Elazığ, Turkey.

Department of Rheumatology, Medical Faculty of Fırat University, Elazığ, Turkey.

出版信息

Arch Rheumatol. 2017 Nov 27;33(3):288-294. doi: 10.5606/ArchRheumatol.2018.6648. eCollection 2018 Sep.

DOI:10.5606/ArchRheumatol.2018.6648

PMID:30632522

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6328211/

Abstract

OBJECTIVES

This study aims to determine the prophylactic and therapeutic efficacy of inhibition of Wnt/β-catenin signaling pathway with paricalcitol in an experimental scleroderma model created with bleomycin (BLM).

MATERIALS AND METHODS

Sixty female BALB/c mice (8-week old and weighing 25 g to 30 g) were divided into six groups as prophylactic-early [group 1 (control I)], sham I (group 2), paricalcitol I (group 3), therapeutic-late [group 4 (control II)], sham II (group 5), and paricalcitol II (group 6) groups. Subcutaneous BLM (100 μg/day) injections were used to induce dermal fibrosis and paricalcitol (0.3 μg/kg/day) was applied subcutaneously to BLM-injected mice during the first three weeks for preventive interventions and in the second three weeks for therapeutic interventions. Tissue samples were harvested for subsequent pathological and real-time polymerase chain reaction analysis. Tissue transforming growth factor-beta 1, axin-1, and Wnt-2 messenger ribonucleic acid expressions were determined by real-time polymerase chain reaction.

RESULTS

Repeated BLM applications increased the dermal inflammatory cell infiltration and dermal thickness, and led to dermal fibrosis, in both early and late stages. Similarly, transforming growth factor-beta 1, axin-1, and Wnt-2 expressions were significantly increased in the sham groups compared to the own control group (p<0.05 for all). Contrarily, prophylactic and therapeutic paricalcitol applications decreased the transforming growth factor-beta 1, axin-1, and Wnt-2 messenger ribonucleic acid expressions compared to the own sham group (p<0.05 for all). In addition, the regressions in dermal necro-inflammation and dermal fibrosis on pathological views were also observed in the paricalcitol applied groups.

CONCLUSION

In this model, increased axin-1 and Wnt-2 messenger ribonucleic acid expressions suggest that Wnt/β-catenin pathway is active in dermal fibrosis.

摘要

目的

本研究旨在确定在博来霉素（BLM）诱导的实验性硬皮病模型中，帕立骨化醇抑制Wnt/β-连环蛋白信号通路的预防和治疗效果。

材料与方法

将60只8周龄、体重25至30克的雌性BALB/c小鼠分为六组，即预防早期组[第1组（对照I）]、假手术I组（第2组）、帕立骨化醇I组（第3组）、治疗晚期组[第4组（对照II）]、假手术II组（第5组）和帕立骨化醇II组（第6组）。皮下注射BLM（100μg/天）诱导皮肤纤维化，在前三周对注射BLM的小鼠皮下注射帕立骨化醇（0.3μg/kg/天）进行预防性干预，后三周进行治疗性干预。采集组织样本用于后续病理和实时聚合酶链反应分析。通过实时聚合酶链反应测定组织转化生长因子-β1、轴抑制蛋白-1和Wnt-2信使核糖核酸表达。

结果

重复应用BLM在早期和晚期均增加了皮肤炎性细胞浸润和皮肤厚度，并导致皮肤纤维化。同样，与各自的对照组相比，假手术组中转化生长因子-β1、轴抑制蛋白-1和Wnt-2表达显著增加（均p<0.05）。相反，与各自的假手术组相比，预防性和治疗性应用帕立骨化醇降低了转化生长因子-β1、轴抑制蛋白-1和Wnt-2信使核糖核酸表达（均p<0.05）。此外，在应用帕立骨化醇的组中，在病理观察中也观察到皮肤坏死性炎症和皮肤纤维化的消退。