Editors' ChoicePharmacology

Statins for Wound Healing

Sci. Signal.  19 Jan 2010:
Vol. 3, Issue 105, pp. ec24
DOI: 10.1126/scisignal.3105ec24

Skin and other epithelial surfaces have a remarkable capacity to heal in response to wounding. In the skin, wound healing involves the migration of keratinocytes into the wounded area, their activation, and finally epithelialization and wound closure. Vukelic et al. use a pharmacological approach to show that farnesyl pyrophosphate (FPP) inhibits keratinocyte activation and wound epithelialization. Glucocorticoid receptors (GR) are known to inhibit wound healing, partially through repression of the expression of genes encoding keratins in keratinocytes. Primary human keratinocytes treated with mevastatin, which inhibits HMG-CoA reductase preventing FPP synthesis, showed limited GR activation, monitored by the nuclear accumulation of phosphorylated GRs. In contrast, treatment of the cells with dexamethasone (a GR agonist), zaragozic acid (ZGA, a squalene synthetase inhibitor that increases the abundance of FPP), or FPP activated GR, which was determined from the nuclear accumulation in nontransfected keratinocytes and the activities of two GR reporter genes (one activated and one repressed) in transfected keratinocytes. Chromatin immunoprecipitation experiments confirmed that GR was bound to the keratin 6 (K6) reporter gene promoter, which is repressed by GR, in cells treated with FPP. In a scratch assay with primary human keratinocytes, treatment of the cells with ZGA, FPP, or B581 (a compound that blocks protein farnesylation and increases FPP) inhibited keratinocyte migration, whereas coapplication of a GR antagonist reversed the inhibition. Treatment with mevastatin increased migration, which was blocked by coapplication of FPP. The authors also tested the effect of FPP and mevastatin in wound closure in a human skin organ culture punch biopsy and found that topical application of FPP or ZGA inhibited epithelialization and K6 production at the wounded area, whereas application of mevastatin promoted epithelialization and K6 production, an effect blocked by coapplication of FPP. These results suggest that statins may be useful in promoting epithelial wound healing and that inhibition of GR activity by blocking production of FPP may contribute to this activity.

S. Vukelic, O. Stojadinovic, I. Pastar, C. Vouthounis, A. Krzyzanowska, S. Das, H. H. Samuels, M. Tomic-Canic, Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. J. Biol. Chem. 285, 1980–1988 (2010). [Abstract] [Full Text]