Rheumatology Center, PLA General Hospital of Chengdu Military Area Command, Chengdu, Sichuan Province, PR China; National TCM Rehab Center, PLA General Hospital of Chengdu Military Area Command, Chengdu, Sichuan Province, PR China; Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou, Guangdong Province, PR China.
Med Hypotheses. 2013 Nov;81(5):948-53. doi: 10.1016/j.mehy.2013.09.001. Epub 2013 Sep 8.
Angiogenesis is particularly driven in the synovial microenvironment of Rheumatoid arthritis (RA), and considered as the fundamental cause for the persistent injury and chronic damage. Therefore, exploring the pathomechanism of synovial angiogenesis may provide promising prospects for vascular-targeting treatment of RA. The noval family of Scube proteins is confirmed to overlap significantly in structure characterized by epidermal growth factor (EGF)-like domains and CUB (complement subcomponents C1r/C1s, Uegf, bone morphogenetic protein-1) domain. As secreted glycoprotein and peripheral membrane protein, Scube increases its serum level in response to stimuli of inflammation and hypoxia. In rheumatoid angiogenesis-related signaling system defined by hedgehog (Hh), transforming growth factor (TGF)β and bone morphogenetic protein 2 (BMP2), Scube1 and 2 antagonize BMP2 signaling, suppressing BMP2-induced phospho-Smad1/5/8 level in vivo. Scube3 functions as an endogenous TGFβ receptor ligand, increasing Smad2/3 phosphorylation, and thus upregulates target genes involved in angiogenesis. Via obligate assistance of Scube1 and 3, Scube2 plays a center role to recruit dually lipid-modified Hh transferred from Dispatched A (DispA), increasing Hh secretion by promoting its solubility. These findings support the hypothesis that Scube may regulate synovial angiogenesis may be the ideal vascular targets for anti-rheumatic treatment of RA.
血管生成在类风湿关节炎（RA）的滑膜微环境中特别活跃，被认为是持续性损伤和慢性损害的根本原因。因此，探索滑膜血管生成的发病机制可能为 RA 的血管靶向治疗提供有前景的前景。Scube 蛋白家族的novel 结构与表皮生长因子（EGF）样结构域和 CUB（补体亚成分 C1r/C1s、Uegf、骨形态发生蛋白-1）结构域重叠，结构特征显著。作为一种分泌型糖蛋白和外周膜蛋白，Scube 在炎症和缺氧刺激下血清水平升高。在由 hedgehog（Hh）、转化生长因子（TGF）β和骨形态发生蛋白 2（BMP2）定义的类风湿血管生成相关信号系统中，Scube1 和 2 拮抗 BMP2 信号，抑制体内 BMP2 诱导的磷酸化 Smad1/5/8 水平。Scube3 作为内源性 TGFβ受体配体，增加 Smad2/3 磷酸化，从而上调参与血管生成的靶基因。通过 Scube1 和 3 的强制性辅助，Scube2 发挥中心作用，招募从 Dispatched A（DispA）转移的双重脂质修饰的 Hh，通过促进其可溶性来增加 Hh 的分泌。这些发现支持了这样一种假设，即 Scube 可能调节滑膜血管生成，可能是 RA 抗风湿治疗的理想血管靶点。
