Periostin facilitates skin sclerosis via PI3K/Akt dependent mechanism in a mouse model of scleroderma.
Periostin facilitates skin sclerosis via PI3K/Akt dependent mechanism in a mouse model of scleroderma.
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DOI：
10.1371/journal.pone.0041994
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Katayama I
中科院分区：
文献类型：
--
作者：
Yang L;Serada S;Fujimoto M;Terao M;Kotobuki Y;Kitaba S;Matsui S;Kudo A;Naka T;Murota H;Katayama I
骨膜蛋白是一种新的基质细胞蛋白，近年来被报道在组织重塑中起重要作用，并且在纤维化条件下高度表达。本研究旨在评估骨膜蛋白在硬皮病中的作用。使用来自患者和健康供体的皮肤，通过免疫组织化学和免疫印迹分析评估骨膜蛋白的表达。此外，我们研究了骨膜蛋白-/-（PN-/-）和野生型（WT）小鼠，以阐明骨膜蛋白在硬皮病中的作用。为了诱导小鼠皮肤硬化，小鼠皮下注射博来霉素，而未处理的对照组注射磷酸盐缓冲盐水。通过组织学分析以及体内和体外促纤维化细胞因子和细胞外基质蛋白表达水平的测量，比较了PN-/-和WT小鼠中博莱霉素诱导的纤维化变化。为了确定参与骨膜蛋白信号传导的下游途径，在体外使用受体中和抗体和信号转导抑制剂。与健康供体相比，在硬皮病患者的病变皮肤中观察到骨膜蛋白的表达升高。尽管WT小鼠在博来霉素治疗后表现出明显的皮肤硬化，骨膜蛋白表达增加，肌成纤维细胞数量增加，但PN-/-小鼠对这些变化表现出抵抗力。在体外，来自PN−/−小鼠的真皮成纤维细胞显示转化生长因子β 1（TGFβ1）诱导的α平滑肌动蛋白和I型前胶原α 1（Col 1 α1）的转录表达降低。此外，重组小鼠periostin在体外可直接诱导Col 1 α1的表达，而这种作用可通过阻断αv整合素介导的PI 3 K/Akt信号通路而被抑制，阻断剂包括抗αv功能性阻断抗体和PI 3 K/Akt激酶抑制剂LY 294002。骨膜蛋白在博莱霉素诱导的小鼠硬皮病的发病机制中起重要作用。骨膜蛋白可能是治疗硬皮病的一个潜在靶点。
Periostin, a novel matricellular protein, is recently reported to play a crucial role in tissue remodeling and is highly expressed under fibrotic conditions. This study was undertaken to assess the role of periostin in scleroderma. Using skin from patients and healthy donors, the expression of periostin was assessed by immunohistochemistry and immunoblotting analyses. Furthermore, we investigated periostin−/− (PN−/−) and wild-type (WT) mice to elucidate the role of periostin in scleroderma. To induce murine cutaneous sclerosis, mice were subcutaneously injected with bleomycin, while untreated control groups were injected with phosphate-buffered saline. Bleomycin-induced fibrotic changes were compared in PN−/− and WT mice by histological analysis as well as by measurements of profibrotic cytokine and extracellular matrix protein expression levels in vivo and in vitro. To determine the downstream pathway involved in periostin signaling, receptor neutralizing antibody and signal transduction inhibitors were used in vitro. Elevated expression of periostin was observed in the lesional skin of patients with scleroderma compared with healthy donors. Although WT mice showed marked cutaneous sclerosis with increased expression of periostin and increased numbers of myofibroblasts after bleomycin treatment, PN−/− mice showed resistance to these changes. In vitro, dermal fibroblasts from PN−/− mice showed reduced transcript expression of alpha smooth actin and procollagen type-I alpha 1 (Col1α1) induced by transforming growth factor beta 1 (TGFβ1). Furthermore, recombinant mouse periostin directly induced Col1α1 expression in vitro, and this effect was inhibited by blocking the αv integrin-mediated PI3K/Akt signaling either with anti-αv functional blocking antibody or with the PI3K/Akt kinase inhibitor LY294002. Periostin plays an essential role in the pathogenesis of Bleomycin-induced scleroderma in mice. Periostin may represent a potential therapeutic target for human scleroderma.
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影响因子：
4.1
作者：
Norris RA;Moreno-Rodriguez R;Hoffman S;Markwald RR
通讯作者：
Markwald RR
影响因子：
4.9
作者：
McCann MR;Monemdjou R;Ghassemi-Kakroodi P;Fahmi H;Perez G;Liu S;Shi-Wen X;Parapuram SK;Kojima F;Denton CP;Abraham DJ;Martel-Pelletier J;Crofford LJ;Leask A;Kapoor M
通讯作者：
Kapoor M
DOI：
10.1152/ajpheart.00370.2004
发表时间：
2005-01-01
影响因子：
4.8
作者：
Ikonomidis, JS;Hendrick, JW;Spinale, FG
通讯作者：
Spinale, FG
影响因子：
--
作者：
Murota, H;Hamasaki, Y;Matsuyama, T
通讯作者：
Matsuyama, T
影响因子：
--
作者：
Leask, A;Abraham, DJ;Connolly, MK
通讯作者：
Connolly, MK