Adenosine A(2a) Receptor Blockade Diminishes Wnt/beta-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis

作者：Zhang, Jin; Corciulo, Carmen; Liu, Hailing; Wilder, Tuere; Ito, Mayumi; Cronstein, Bruce^*

来源：American Journal Of Pathology, 2017, 187(9): 1935-1944.

DOI：10.1016/j.ajpath.2017.05.005

• EPITHELIAL-MESENCHYMAL TRANSITION
• BETA-CATENIN
• PHARMACOLOGICAL BLOCKADE
• SYSTEMIC-SCLEROSIS
• CYCLIC-AMP
• TGF-BETA
• FIBROBLASTS
• MYOFIBROBLASTS
• COLLAGEN
• PATHWAY

Adenosine A(2a) receptor (A(2a)R) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A(2a)R and WNT/beta-catenin signaling pathway. In in vitro studies, A(2a)R signaling for collagen III expression was mediated by WNT/beta-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A(2a)R and Wnt/beta-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt-signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A(2a)R antagonist istradefylline (KW6002) or vehicle. Dermal fibrosis was quantitated and nuclear translocation of beta-catenin in fibroblasts was assessed by double-staining for Green fluorescent protein or dephosphorylated beta-catenin or beta-catenin phosphorylated at Ser552, and vimentin. KW6002 significantly reduced skin thickness, skinfold thickness, breaking tension, dermal hydroxyproline content, myofibroblast accumulation, and collagen alignment in bleomycin-induced dermal fibrosis. Also, there was increased expression of Tcf/Lef:H2B-GFP reporter in bleomycin-induced dermal fibrosis, an effect that was diminished by treatment with KW6002. Moreover, KW6002 significantly inhibited nuclear translocation of Tcf/Lef:H2B-GFP reporter, as well as dephosphorylated beta-catenin and beta-catenin phosphorylated at Ser552. Our work supports the hypothesis that pharmacologic blockade of A(2a)R inhibits the WNT/beta-catenin signaling pathway, contributing to its capacity to inhibit dermal fibrosis in diseases such as scleroderma.

• 出版日期2017-9
• 单位宁波市医疗中心李惠利医院; 宁波大学