Matrix metalloproteinase inhibition delays wound healing and blocks the latent transforming growth factor-beta1-promoted myofibroblast formation and function

Wound Repair Regen. Mar-Apr 2010;18(2):223-34. doi: 10.1111/j.1524-475X.2010.00574.x. Epub 2010 Mar 12.

Abstract

The ability to regulate wound contraction is critical for wound healing as well as for pathological contractures. Matrix metalloproteinases (MMPs) have been demonstrated to be obligatory for normal wound healing. This study examined the effect that the broad-spectrum MMP inhibitor BB-94 has when applied topically to full-thickness skin excisional wounds in rats and its ability to inhibit the promotion of myofibroblast formation and function by the latent transforming-growth factor-beta1 (TGF-beta1). BB-94 delayed wound contraction, as well as all other associated aspects of wound healing examined, including myofibroblast formation, stromal cell proliferation, blood vessel formation, and epithelial wound coverage. Interestingly, BB-94 dramatically increased the level of latent and active MMP-9. The increased levels of active MMP-9 may eventually overcome the ability of BB-94 to inhibit this MMP and may explain why wound contraction and other associated events of wound healing were only delayed and not completely inhibited. BB-94 was also found to inhibit the ability of latent TGF-beta1 to promote the formation and function of myofibroblasts. These results suggest that BB-94 could delay wound closure through a twofold mechanism; by blocking keratinocyte migration and thereby blocking the necessary keratinocyte-fibroblast interactions needed for myofibroblast formation and by inhibiting the activation of latent TGF-beta1.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Fibroblasts / drug effects
  • Matrix Metalloproteinase 9 / drug effects
  • Neovascularization, Physiologic / drug effects
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Protease Inhibitors / pharmacology*
  • Rats
  • Skin / cytology*
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Thiophenes / pharmacology*
  • Transforming Growth Factor beta1 / antagonists & inhibitors
  • Wound Healing / drug effects*
  • Wound Healing / physiology*

Substances

  • Protease Inhibitors
  • Thiophenes
  • Transforming Growth Factor beta1
  • Phenylalanine
  • batimastat
  • Matrix Metalloproteinase 9