Data_Sheet_1_Loss of Smad7 Promotes Inflammation in Rheumatoid Arthritis.PDF

Objective: Smad7 is an inhibitory Smad and plays a protective role in many inflammatory diseases. However, the roles of Smad7 in rheumatoid arthritis (RA) remain unexplored, which were investigated in this study.
Methods: The activation of TGF-β/Smad signaling was examined in synovial tissues of patients with RA. The functional roles and mechanisms of Smad7 in RA were determined in a mouse model of collagen-induced arthritis (CIA) in Smad7 wild-type (WT) and knockout (KO) CD-1 mice, a strain resistant to autoimmune arthritis induction.
Results: TGF-β/Smad3 signaling was markedly activated in synovial tissues of patients with RA, which was associated with the loss of Smad7, and enhanced Th17 and Th1 immune response. The potential roles of Smad7 in RA were further investigated in a mouse model of CIA in Smad7 WT/KO CD-1 mice. As expected, Smad7-WT CD-1 mice did not develop CIA. Surprisingly, CD-1 mice with Smad7 deficiency developed severe arthritis including severe joint swelling, synovial hyperplasia, cartilage damage, massive infiltration of CD3+ T cells and F4/80+ macrophages, and upregulation of proinflammatory cytokines IL-1β, TNFα, and MCP-1. Further studies revealed that enhanced arthritis in Smad7 KO CD-1 mice was associated with increased Th1, Th2 and, importantly, Th17 over the Treg immune response with overactive TGF-β/Smad3 and proinflammatory IL-6 signaling in the joint tissues.
Conclusions: Smad7 deficiency increases the susceptibility to autoimmune arthritis in CD-1 mice. Enhanced TGF-β/Smad3-IL-6 signaling and Th17 immune response may be a mechanism through which disrupted Smad7 causes autoimmune arthritis in CD-1 mice.

研究目的：Smad7是一种抑制性Smad蛋白，在多种炎症性疾病中发挥保护作用。然而，Smad7在类风湿关节炎（rheumatoid arthritis, RA）中的作用仍未明确，本研究就此展开探究。
研究方法：本研究检测了RA患者滑膜组织中转化生长因子-β/Smad（TGF-β/Smad）信号通路的激活情况。通过在对自身免疫性关节炎造模具有抗性的Smad7野生型（wild-type, WT）和敲除型（knockout, KO）CD-1小鼠的胶原诱导性关节炎（collagen-induced arthritis, CIA）模型中开展实验，明确了Smad7在RA中的功能作用与调控机制。
研究结果：RA患者滑膜组织中TGF-β/Smad3信号通路显著激活，该现象与Smad7表达缺失、辅助性T细胞17（Th17）及辅助性T细胞1（Th1）免疫应答增强密切相关。本研究进一步在Smad7 WT/KO CD-1小鼠的CIA模型中探究了Smad7在RA中的潜在作用。正如预期，Smad7 WT CD-1小鼠未诱发CIA。令人意外的是，Smad7缺陷型CD-1小鼠出现了严重关节炎症状，包括重度关节肿胀、滑膜增生、软骨损伤、CD3+ T细胞与F4/80+巨噬细胞大量浸润，以及促炎细胞因子IL-1β、TNFα及MCP-1的表达水平上调。进一步研究表明，Smad7 KO CD-1小鼠的关节炎症状加重，与关节组织中TGF-β/Smad3及促炎IL-6信号通路过度激活、Th1、Th2及关键的Th17免疫应答相较于调节性T细胞（Treg）占优相关。
研究结论：Smad7缺陷可增强CD-1小鼠对自身免疫性关节炎的易感性。TGF-β/Smad3-IL-6信号通路过度激活与Th17免疫应答增强，可能是Smad7功能缺失导致CD-1小鼠发生自身免疫性关节炎的潜在分子机制。