Effects of recombinant human tissue inhibitor of metalloproteinases-2 (rh-TIMP-2) on migration of epidermal keratinocytes in vitro and wound healing in vivo

J Dermatol. 2003 Mar;30(3):165-72. doi: 10.1111/j.1346-8138.2003.tb00367.x.


Tissue inhibitors of metalloproteinases (TIMP), common inhibitors of matrix proteinases, have cell-promoting activity. We studied the effects of recombinant human tissue inhibitor of metalloproteinases-2 (rh-TIMP-2) on the migration of normal human epidermal keratinocytes (NHEK). An in vitro migration assay revealed that rh-TIMP-2 enhanced random migration (up to 170%, p<0.05) in a dose-dependent manner. When we applied rh-TIMP-2 solution (20 microg/20 microl/wound) daily to full-thickness wounds made with an 8-mm punch on the backs of healthy (n=8), aged (n=9), and diabetic (n=15) rodents, we observed faster wound closure (p<0.05) than in vehicle-treated controls. Accelerated wound closure was dose-dependent (0-20 microg/wound) in diabetic mice (n=6), and the optimal concentration was 10-20 microg of rh-TIMP-2/wound. Histological examinations performed on days 0, 5, 10, 15, and 20 in diabetic mice revealed faster migration of epidermal keratinocytes from wound edges. These results suggest that rh-TIMP-2 plays an important role in wound healing.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cell Movement / drug effects*
  • Cells, Cultured
  • Diabetes Mellitus / drug therapy
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Epidermis / drug effects
  • Female
  • Humans
  • Keratinocytes / drug effects*
  • Keratinocytes / physiology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Probability
  • Recombination, Genetic
  • Reference Values
  • Sensitivity and Specificity
  • Tissue Inhibitor of Metalloproteinase-2 / pharmacology*
  • Wound Healing / drug effects*
  • Wound Healing / physiology
  • Wounds and Injuries / drug therapy*
  • Wounds and Injuries / pathology


  • Tissue Inhibitor of Metalloproteinase-2