Journal of Molecular Medicine

, Volume 86, Issue 8, pp 961–969 | Cite as

ADAM12: a potential target for the treatment of chronic wounds

  • Asheesh Harsha
  • Olivera Stojadinovic
  • Harold Brem
  • Atsuko Sehara-Fujisawa
  • Ulla Wewer
  • Cynthia A. Loomis
  • Carl P. Blobel
  • Marjana Tomic-Canic
Original Article

Abstract

Wound healing is a complex process involving multiple cellular events, including cell proliferation, migration, and tissue remodeling. A disintegrin and metalloprotease 12 (ADAM12) is a membrane-anchored metalloprotease, which has been implicated in activation–inactivation of growth factors that play an important role in wound healing, including heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and insulin growth factor (IGF) binding proteins. Here, we report that expression of ADAM12 is fivefold upregulated in the nonhealing edge of chronic ulcers compared to healthy skin, based on microarrays of biopsies taken from five patients and from healthy controls (p = 0.013). The increase in ADAM12 expression in chronic ulcers was confirmed by quantitative real-time polymerase chain reaction (RT-PCR). Moreover, immunohistochemical analysis demonstrated a pronounced increase in the membranous and intracellular signal for ADAM12 in the epidermis of chronic wounds compared to healthy skin. These findings, coupled with our previous observations that lack of keratinocyte migration contributes to the pathogenesis of chronic ulcers, prompted us to evaluate how the absence of ADAM12 affects the migration of mouse keratinocytes. Skin explants from newborn ADAM12−/− or wild-type (WT) mice were used to quantify keratinocyte migration out of the explants over a period of 7 days. We found a statistically significant increase in the migration of ADAM12−/− keratinocytes compared to WT control (p = 0.0014) samples. Taken together, the upregulation of ADAM12 in chronic wounds and the increased migration of keratinocytes in the absence of ADAM12 suggest that ADAM12 is an important mediator of wound healing. We hypothesize that increased expression of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration and that topical ADAM12 inhibitors may therefore prove useful for the treatment of chronic wounds.

Keywords

ADAM12 Chronic ulcers Wound healing Keratinocyte migration 

Notes

Acknowledgments

Our research is supported by the National Institutes of Health grants GM64750 to CB, and NR008029 to MT-C. We thank Irena Pastar for help with quantitative RT-PCR and all members of Tomic’s and Blobel’s lab for their support.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Asheesh Harsha
    • 1
  • Olivera Stojadinovic
    • 2
  • Harold Brem
    • 3
  • Atsuko Sehara-Fujisawa
    • 4
  • Ulla Wewer
    • 5
  • Cynthia A. Loomis
    • 6
  • Carl P. Blobel
    • 1
  • Marjana Tomic-Canic
    • 2
  1. 1.Arthritis and Tissue Degeneration ProgramHospital for Special Surgery at Weill Medical College of Cornell UniversityNew YorkUSA
  2. 2.Tissue Repair Lab, Tissue Engineering, Repair and Regeneration ProgramHospital for Special Surgery at Weill Medical College of Cornell UniversityNew YorkUSA
  3. 3.Wound Healing Program, Department of SurgeryColumbia University College of Physicians and SurgeonsNew YorkUSA
  4. 4.Department of Molecular OncologyKyoto University Graduate School of MedicineKyotoJapan
  5. 5.Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
  6. 6.New York University School of MedicineNew YorkUSA

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