Lin Yuh-Charn, Roffler Steve R, Yan Yu-Ting, Yang Ruey-Bing
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
J Bone Miner Res. 2015 Jul;30(7):1255-67. doi: 10.1002/jbmr.2451.
Signal peptide-CUB-EGF domain-containing protein 2 (SCUBE2) belongs to a secreted and membrane-tethered multidomain SCUBE protein family composed of three members found in vertebrates and mammals. Recent reports suggested that zebrafish scube2 could facilitate sonic hedgehog (Shh) signaling for proper development of slow muscle. However, whether SCUBE2 can regulate the signaling activity of two other hedgehog ligands (Ihh and Dhh), and the developmental relevance of the SCUBE2-induced hedgehog signaling in mammals remain poorly understood. In this study, we first showed that as compared with SCUBE1 or SCUBE3, SCUBE2 is the most potent modulator of IHH signaling in vitro. In addition, gain and loss-of-function studies demonstrated that SCUBE2 exerted an osteogenic function by enhancing Ihh-stimulated osteoblast differentiation in the mouse mesenchymal progenitor cells. Consistent with these in vitro studies and the prominent roles of Ihh in coordinating skeletogenesis, genetic ablation of Scube2 (-/-) caused defective endochondral bone formation and impaired Ihh-mediated chondrocyte differentiation and proliferation as well as osteoblast differentiation of -/- bone-marrow mesenchymal stromal-cell cultures. Our data demonstrate that Scube2 plays a key regulatory role in Ihh-dependent endochondral bone formation.
含信号肽-CUB-表皮生长因子结构域蛋白2（SCUBE2）属于一个分泌型且与膜相连的多结构域SCUBE蛋白家族，该家族由在脊椎动物和哺乳动物中发现的三个成员组成。最近的报道表明，斑马鱼的scube2可以促进音猬因子（Shh）信号传导，以确保慢肌的正常发育。然而，SCUBE2是否能够调节另外两种刺猬因子配体（Ihh和Dhh）的信号活性，以及SCUBE2诱导的刺猬因子信号传导在哺乳动物发育中的相关性仍知之甚少。在本研究中，我们首先表明，与SCUBE1或SCUBE3相比，SCUBE2在体外是最有效的IHH信号调节剂。此外，功能获得和功能丧失研究表明，SCUBE2通过增强Ihh刺激的小鼠间充质祖细胞中的成骨细胞分化发挥成骨功能。与这些体外研究以及Ihh在协调骨骼发生中的重要作用一致，Scube2基因敲除（-/-）导致软骨内骨形成缺陷，Ihh介导的软骨细胞分化和增殖受损，以及-/-骨髓间充质基质细胞培养物的成骨细胞分化受损。我们的数据表明，Scube2在Ihh依赖性软骨内骨形成中起关键调节作用。
