BMP2 inhibits TGF-β-induced pancreatic stellate cell activation and extracellular matrix formation
BMP2 inhibits TGF-β-induced pancreatic stellate cell activation and extracellular matrix formation
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BMP2 抑制TGF-β 诱导的胰腺星状细胞活化和细胞外基质形成。
DOI：
10.1152/ajpgi.00306.2012
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发表时间：
2013-05-01
影响因子：
4.5
通讯作者：
Ko, Tien C.
中科院分区：
文献类型：
--
作者：
Gao, Xuxia;Cao, Yanna;Ko, Tien C.
转化生长因子（transforming growth factor，TGF）-β激活胰腺星状细胞（pancreatic stellate cells，PSC）是胰腺纤维化发展的关键步骤，是慢性胰腺炎（chronic pancreatitis，CP）的常见病理特征。骨形态发生蛋白（BMP）是TGF-β超家族的成员，与TGF-β相反，在肾、肺和肝中具有抗纤维化功能。然而，目前尚不清楚BMP是否在胰腺中具有抗纤维化作用。本研究旨在使用体内CP模型和体外PSC模型研究BMP在胰腺中的潜在抗纤维化作用。CP是通过在成年瑞士韦伯斯特小鼠中重复腹膜内注射雨蛙肽诱导的。对照组小鼠接受生理盐水注射。与对照组相比，雨蛙肽注射诱导腺泡损伤和纤维化进展呈时间依赖性增加，炎症稳定增加。蛙皮素注射液还诱导细胞外基质（ECM）蛋白纤连蛋白和α-平滑肌肌动蛋白（α-SMA）阳性星状细胞（PSC）的增加。接受雨蛙肽注射的小鼠显示BMP 2蛋白水平和磷酸化Smad 1水平增加至4周，然后在8周下降至与对照组相似的水平。在体外，培养分离的小鼠和人PSC，并用BMP 2预处理，然后用TGF-β处理。BMP 2预处理抑制TGF-β诱导的α-SMA、纤连蛋白和Ia型胶原表达。用小干扰RNA（siRNA）敲除Smad 1可逆转BMP 2对TGF-β诱导的α-SMA和FN表达的抑制作用。因此，BMP 2通过Smad 1信号通路对抗PSC中TGF-β的纤维化功能。
Activation of pancreatic stellate cells (PSCs) by transforming growth factor (TGF)-β is the key step in the development of pancreatic fibrosis, a common pathological feature of chronic pancreatitis (CP). Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have anti-fibrogenic functions, in contrast to TGF-β, in the kidney, lung, and liver. However, it is not known whether BMPs have an anti-fibrogenic role in the pancreas. The current study was designed to investigate the potential anti-fibrogenic role of BMPs in the pancreas using an in vivo CP model and an in vitro PSC model. CP was induced by repetitive intraperitoneal injections of cerulein in adult Swiss Webster mice. The control mice received saline injections. Compared with the control, cerulein injections induced a time-dependent increase in acinar injury and progression of fibrosis and a steady increase in inflammation. Cerulein injections also induced increases of the extracellular matrix (ECM) protein fibronectin and of α-smooth muscle actin (α-SMA)-positive stellate cells (PSCs). The mice receiving cerulein injections showed increased BMP2 protein levels and phosphorylated Smad1 levels up to 4 wk and then declined at 8 wk to similar levels as the control. In vitro, the isolated mouse and human PSCs were cultured and pretreated with BMP2 followed by TGF-β treatment. BMP2 pretreatment inhibited TGF-β-induced α-SMA, fibronectin, and collagen type Ia expression. Knocking down Smad1 with small-interfering RNA reversed the inhibitory effect of BMP2 on TGF-β-induced α-SMA and fibronectin expression. Thus, BMP2 opposes the fibrogenic function of TGF-β in PSCs through the Smad1 signaling pathway.