Farnesyl Pyrophosphate Inhibits Epithelialization and Wound Healing through the Glucocorticoid Receptor

Abstract

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.

Stress-Induced Hormones Cortisol and Epinephrine Impair Wound Epithelization

“…This effect was due to the blockade of FPP's activation of the GR. 9 Taken together, this finding establishes a second, upstream mechanism whereby the stress hormone pathway can be activated in epidermis. The role of FPP in the pathogenesis of chronic wounds and their nonmigratory keratinocytes needs further investigation.…”

“…9 However, studies have shown that enhanced keratinocyte migratory potential is not mediated through the inhibition of cholesterol synthesis despite the disrupted skin barrier. This effect was due to the blockade of FPP's activation of the GR.…”

“…3 Similarly, topical mevastatin, an 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, reduces endogenous levels of FPP and increases epithelization in an ex vivo wound model. 9 Further, inclusion of a b2AR antagonist, timolol, reverses the inhibitory effects of epinephrine on keratinocyte migration and wound epithelization. 6 Systemic administration of a b2AR antagonist accelerates wound epithelization in an in vivo burn wound model.…”

“…Two novel topical treatments, which are typically used to improve cardiovascular health, are proposed to improve wound healing: statins and beta-blockers. 5,9,19 Additionally, topical treatment with metyrapone, an inhibitor of CYP11B1, enhanced keratinocyte migration and wound epithelization.…”

“…A main branch point intermediate in the mevalonate pathway is FPP. 9 FPP can bind GR, thus causing many of the same deleterious effects as GCs during the wound healing process. Each is shown to inhibit keratinocyte migration and wound epithelization through a similar mechanism by targeting expression of the early wound healing markers, keratin 6 and 16.…”