Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.
Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Korea.
Invest Ophthalmol Vis Sci. 2022 Jun 1;63(6):7. doi: 10.1167/iovs.63.6.7.
We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves' orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves' orbital fibroblasts.
Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-β, IL-1β, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed.
The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-β were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-β induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1β or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment.
BMP7 transcript levels were downregulated in Graves' orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-β/SMAD signaling and proinflammatory cytokine production.
我们研究了骨形态发生蛋白 7（BMP7）在格雷夫斯眼病（GO）发病机制中的作用，BMP7 是 TGF-β 超家族的成员。评估了 BMP7 在培养的格雷夫斯眼眶成纤维细胞中的炎症和纤维化治疗作用。
使用实时 PCR 比较来自 GO（n = 12）和正常对照（n = 12）患者的培养眼眶组织外植体中的 BMP7 表达。从 GO（n = 3）和正常对照患者（n = 3）的眼眶结缔组织中培养眼眶成纤维细胞。在刺激 TGF-β、IL-1β 和 TNF-α 之前，用重组人 BMP7（rhBMP7）预处理细胞。通过 Western blot 分析纤维化相关蛋白和炎症细胞因子。还分析了炎症和纤维化中信号分子的激活。
GO 眼眶组织中的 BMP7 mRNA 表达低于对照。rhBMP7 处理抑制 TGF-β诱导的纤维化相关蛋白纤维连接蛋白、胶原 1α 和 α-SMA 的产生，并上调 TGF-β 诱导的 SMAD1/5/8 蛋白表达，而下调 SMAD2/3。rhBMP7 处理阻断了 IL-1β 或 TNF-α 诱导的促炎分子 IL-6、IL-8 和细胞间黏附分子 1（ICAM-1）的增加，rhBMP7 处理抑制了磷酸化 NFκB 和 Akt 的表达。
格雷夫斯眼眶组织中的 BMP7 转录水平下调。外源性 BMP7 治疗对眼眶成纤维细胞中促纤维化蛋白和促炎细胞因子的产生具有抑制作用。我们的结果为 BMP7 作为一种新的潜在治疗剂提供了分子基础，通过拮抗促纤维化 TGF-β/SMAD 信号和促炎细胞因子产生的机制。
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