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

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)961-969
Number of pages9
JournalJournal of Molecular Medicine
Volume86
Issue number8
DOIs
StatePublished - Aug 1 2008
Externally publishedYes

Fingerprint

Disintegrins
Metalloproteases
Wounds and Injuries
Keratinocytes
Wound Healing
Therapeutics
Ulcer
Intercellular Signaling Peptides and Proteins
Epidermal Growth Factor
Skin
Epidermis
Cell Movement
Heparin

Keywords

  • ADAM12
  • Chronic ulcers
  • Keratinocyte migration
  • Wound healing

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Harsha, A., Stojadinovic, O., Brem, H., Sehara-Fujisawa, A., Wewer, U., Loomis, C. A., ... Tomic-Canic, M. (2008). ADAM12: A potential target for the treatment of chronic wounds. Journal of Molecular Medicine, 86(8), 961-969. https://doi.org/10.1007/s00109-008-0353-z

ADAM12 : A potential target for the treatment of chronic wounds. / Harsha, Asheesh; Stojadinovic, Olivera; Brem, Harold; Sehara-Fujisawa, Atsuko; Wewer, Ulla; Loomis, Cynthia A.; Blobel, Carl P.; Tomic-Canic, Marjana.

In: Journal of Molecular Medicine, Vol. 86, No. 8, 01.08.2008, p. 961-969.

Research output: Contribution to journalArticle

Harsha, A, Stojadinovic, O, Brem, H, Sehara-Fujisawa, A, Wewer, U, Loomis, CA, Blobel, CP & Tomic-Canic, M 2008, 'ADAM12: A potential target for the treatment of chronic wounds', Journal of Molecular Medicine, vol. 86, no. 8, pp. 961-969. https://doi.org/10.1007/s00109-008-0353-z
Harsha A, Stojadinovic O, Brem H, Sehara-Fujisawa A, Wewer U, Loomis CA et al. ADAM12: A potential target for the treatment of chronic wounds. Journal of Molecular Medicine. 2008 Aug 1;86(8):961-969. https://doi.org/10.1007/s00109-008-0353-z
Harsha, Asheesh ; Stojadinovic, Olivera ; Brem, Harold ; Sehara-Fujisawa, Atsuko ; Wewer, Ulla ; Loomis, Cynthia A. ; Blobel, Carl P. ; Tomic-Canic, Marjana. / ADAM12 : A potential target for the treatment of chronic wounds. In: Journal of Molecular Medicine. 2008 ; Vol. 86, No. 8. pp. 961-969.
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