Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor.
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.
Vukelic
Sasa
S
Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York, New York 10021, USA.
Stojadinovic
Olivera
O
Pastar
Irena
I
Vouthounis
Constantinos
C
Krzyzanowska
Agata
A
Das
Sharmistha
S
Samuels
Herbert H
HH
Tomic-Canic
Marjana
M
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D053553:Keratin-6 / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism*; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014233:Tricarboxylic Acids / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D053553:Keratin-6; D008024:Ligands; D011106:Polyisoprenyl Phosphates; D011965:Receptors, Glucocorticoid; D012717:Sesquiterpenes; D014233:Tricarboxylic Acids; C075117:squalestatin 1; C012258:mevastatin; C004808:farnesyl pyrophosphate; D008148:Lovastatin; D013186:Farnesyl-Diphosphate Farnesyltransferase