1. ^*Department of Pathology, Ann Arbor, Michigan
2. ^†Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan
3. ^‡Department of Medicinal Chemistry, University of Mississippi, University, Mississippi
4. ^§Department Biological Sciences, California State University, Hayward, California
5. ^§§Departments of Family Medicine, Kern Medical Center, and University of California, Irvine, California
6. ^¶Bethesda Pharmaceuticals, Inc., Bakersfield, California
7. ^#Department of Laboratory Medicine, University of California, San Francisco, California, USA

Correspondence: James Varani, PhD, Department of Pathology, The University of Michigan, 1301 Catherine Road/Box 0602, Ann Arbor, MI 48109. Email: varani@umich.edu

Received 20 March 2003; Revised 12 June 2003; Accepted 26 August 2003.

Abstract

This study was undertaken to evaluate the effects of thiazolidinediones (TZD) on keratinocyte proliferation, motility, and matrix metalloproteinase (MMP) production. Rosiglitazone (a potent TZD) inhibited both proliferation and motility as well as elaboration of MMP-1 and MMP-9. Inhibition was obtained with keratinocytes in monolayer culture and human skin in organ culture. There were significant concentration–response differences in sensitivity of the three keratinocyte responses to treatment with rosiglitazone. In contrast to keratinocytes, dermal fibroblasts were resistant to the effects of rosiglitazone. Treatment of keratinocytes with rosiglitazone did not suppress epidermal growth factor receptor autophosphorylation, but inhibited signaling through the extracellular regulated kinase mitogen-activated protein kinase pathway without a concomitant effect on pathways that lead to c-jun activation. Pioglitazone, another TZD, also suppressed keratinocyte proliferation, although it was less effective than rosiglitazone. An experimental TZD (BP-1107) inhibited keratinocyte proliferation at a much lower concentration than either rosiglitazone or pioglitazone. Because enhanced keratinocyte motility and increased MMP production as well as increased keratinocyte proliferation are thought to contribute to the phenotype of psoriatic lesional skin, we propose that interference with these keratinocyte responses contributes to the previously reported antipsoriatic activity of TZD.