Kobayashi Koichi, Luo Min, Zhang Yue, Wilkes David C, Ge Gaoxiang, Grieskamp Thomas, Yamada Chikaomi, Liu Ting-Chun, Huang Guorui, Basson Craig T, Kispert Andreas, Greenspan Daniel S, Sato Thomas N
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA.
Nat Cell Biol. 2009 Jan;11(1):46-55. doi: 10.1038/ncb1811. Epub 2008 Dec 14.
Secreted Frizzled-related proteins (sFRPs) have emerged as key regulators of a wide range of developmental and disease processes. Most of the known functions of mammalian sFRPs have been attributed to their ability to antagonize Wnt signalling. Recently however, Xenopus laevis and zebrafish sFRP, Sizzled, was shown to function as an antagonist of Chordin processing by Tolloid-like metalloproteinases. This has led to the proposal that sFRPs may function as evolutionarily conserved antagonists of chordinase activities of this class of proteinases. In contrast to this proposal, we show here that the mammalian sFRP, sFRP2, does not affect Chordin processing, but instead, can serve as a direct enhancer of procollagen C proteinase activity of Tolloid-like metalloproteinases. We also show that the level of fibrosis, in which procollagen processing by Tolloid-like proteinases has a rate-limiting role, is markedly reduced in Sfrp2-null mice subjected to myocardial infarction. Importantly, this reduced level of fibrosis is accompanied by significantly improved cardiac function. This study thus uncovers a function for sFRP2 and a potential therapeutic application for sFRP2 antagonism in controlling fibrosis in the infarcted heart.
分泌型卷曲相关蛋白（sFRPs）已成为多种发育和疾病过程的关键调节因子。哺乳动物sFRPs的大多数已知功能都归因于它们拮抗Wnt信号的能力。然而最近，非洲爪蟾和斑马鱼的sFRP即 sizzled，被证明可作为类 tolloid 金属蛋白酶对脊索蛋白加工的拮抗剂。这导致有人提出，sFRPs可能作为这类蛋白酶脊索酶活性在进化上保守的拮抗剂发挥作用。与这一观点相反，我们在此表明，哺乳动物的sFRP即sFRP2，并不影响脊索蛋白的加工，而是可作为类 tolloid 金属蛋白酶原胶原蛋白C蛋白酶活性的直接增强剂。我们还表明，在心肌梗死的Sfrp2基因敲除小鼠中，由类 tolloid 蛋白酶进行的原胶原蛋白加工起限速作用的纤维化水平显著降低。重要的是，这种降低的纤维化水平伴随着心脏功能的显著改善。因此，本研究揭示了sFRP2的一种功能以及sFRP2拮抗作用在控制梗死心脏纤维化方面的潜在治疗应用。
