Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York, New York 10021, USA.
J Biol Chem. 2010 Jan 15;285(3):1980-8. doi: 10.1074/jbc.M109.016741. Epub 2009 Nov 10.
Farnesyl pyrophosphate (FPP), a key intermediate in the mevalonate pathway and protein farnesylation, can act as an agonist for several nuclear hormone receptors. Here we show a novel mechanism by which FPP inhibits wound healing acting as an agonist for glucocorticoid receptor (GR). Elevation of endogenous FPP by the squalene synthetase inhibitor zaragozic acid A (ZGA) or addition of FPP to the cell culture medium results in activation and nuclear translocation of the GR, a known wound healing inhibitor. We used functional studies to evaluate the effects of FPP on wound healing. Both FPP and ZGA inhibited keratinocyte migration and epithelialization in vitro and ex vivo. These effects were independent of farnesylation and indicate that modulation of FPP levels in skin may be beneficial for wound healing. FPP inhibition of keratinocyte migration and wound healing proceeds, in part, by repression of the keratin 6 gene. Furthermore, we show that the 3-hydroxy-3-methylglutaryl-CoA-reductase inhibitor mevastatin, which blocks FPP formation, not only promotes epithelialization in acute wounds but also reverses the effect of ZGA on activation of the GR and inhibition of epithelialization. We conclude that FPP inhibits wound healing by acting as a GR agonist. Of special interest is that FPP is naturally present in cells prior to glucocorticoid synthesis and that FPP levels can be further altered by the statins. Therefore, our findings may provide a better understanding of the pleiotropic effects of statins as well as molecular mechanisms by which they may accelerate wound healing.
法呢基焦磷酸（FPP）是甲羟戊酸途径和蛋白质法尼基化的关键中间产物，可作为几种核激素受体的激动剂。在这里，我们展示了 FPP 通过充当糖皮质激素受体（GR）的激动剂来抑制伤口愈合的新机制。角鲨烯合酶抑制剂扎拉戈酸 A（ZGA）升高内源性 FPP 或向细胞培养基中添加 FPP 会导致 GR 的激活和核易位，GR 是一种已知的伤口愈合抑制剂。我们使用功能研究来评估 FPP 对伤口愈合的影响。FPP 和 ZGA 均抑制体外和离体角质形成细胞迁移和上皮化。这些作用不依赖于法尼基化，并表明皮肤中 FPP 水平的调节可能有益于伤口愈合。FPP 通过抑制角蛋白 6 基因的表达来抑制角质形成细胞迁移和伤口愈合。此外，我们表明，3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂洛伐他汀可阻断 FPP 的形成，不仅可促进急性伤口的上皮化，还可逆转 ZGA 对 GR 激活和上皮化抑制的作用。我们得出结论，FPP 通过充当 GR 激动剂来抑制伤口愈合。特别有趣的是，FPP 在糖皮质激素合成之前就存在于细胞中，并且他汀类药物可以进一步改变 FPP 水平。因此，我们的发现可能有助于更好地理解他汀类药物的多效作用以及它们可能加速伤口愈合的分子机制。
