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Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor.
J Biol Chem. 2010 Jan 15; 285(3):1980-8.JB

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.

Authors+Show Affiliations

Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York, New York 10021, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19903814

Citation

Vukelic, Sasa, et al. "Farnesyl Pyrophosphate Inhibits Epithelialization and Wound Healing Through the Glucocorticoid Receptor." The Journal of Biological Chemistry, vol. 285, no. 3, 2010, pp. 1980-8.
Vukelic S, Stojadinovic O, Pastar I, et al. Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. J Biol Chem. 2010;285(3):1980-8.
Vukelic, S., Stojadinovic, O., Pastar, I., Vouthounis, C., Krzyzanowska, A., Das, S., Samuels, H. H., & Tomic-Canic, M. (2010). Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. The Journal of Biological Chemistry, 285(3), 1980-8. https://doi.org/10.1074/jbc.M109.016741
Vukelic S, et al. Farnesyl Pyrophosphate Inhibits Epithelialization and Wound Healing Through the Glucocorticoid Receptor. J Biol Chem. 2010 Jan 15;285(3):1980-8. PubMed PMID: 19903814.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. AU - Vukelic,Sasa, AU - Stojadinovic,Olivera, AU - Pastar,Irena, AU - Vouthounis,Constantinos, AU - Krzyzanowska,Agata, AU - Das,Sharmistha, AU - Samuels,Herbert H, AU - Tomic-Canic,Marjana, Y1 - 2009/11/10/ PY - 2009/11/12/entrez PY - 2009/11/12/pubmed PY - 2010/2/9/medline SP - 1980 EP - 8 JF - The Journal of biological chemistry JO - J Biol Chem VL - 285 IS - 3 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/19903814/Farnesyl_pyrophosphate_inhibits_epithelialization_and_wound_healing_through_the_glucocorticoid_receptor_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)64906-9 DB - PRIME DP - Unbound Medicine ER -