Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-γ, normalizes epidermal homeostasis in a murine hyperproliferative disease model

Authors

  • Marianne Demerjian,

    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
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  • Mao-Qiang Man,

    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
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  • Eung-Ho Choi,

    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
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  • Barbara E. Brown,

    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
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  • Debra Crumrine,

    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
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  • Sandra Chang,

    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
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  • Theodora Mauro,

    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
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  • Peter M. Elias,

    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
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  • Kenneth R. Feingold

    Corresponding author
    1. Department of Dermatology, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA;
    2. Department of Medicine, University of California San Francisco and VA Medical Center San Francisco, San Francisco, CA, USA
      Kenneth R. Feingold, MD
      V. A. Medical Center
      Metabolism Section (111F)
      4150 Clement St.
      San Francisco, CA 94121
      USA
      Tel.: +1 415 750 2005
      Fax: +1 415 751 6927
      E-mail: kfngld@itsa.ucsf.edu
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Kenneth R. Feingold, MD
V. A. Medical Center
Metabolism Section (111F)
4150 Clement St.
San Francisco, CA 94121
USA
Tel.: +1 415 750 2005
Fax: +1 415 751 6927
E-mail: kfngld@itsa.ucsf.edu

Abstract

Abstract:  In a murine model of epidermal hyperplasia reproducing some of the abnormalities of several common skin disorders, we previously demonstrated the antiproliferative and pro-differentiating effects of peroxisome proliferator-activated receptor (PPAR)α, PPARβ/δ, and liver X receptor activators. Unlike other subgroups of PPAR activators, thiazolidinediones (TZDs), a family of PPARγ ligands, did not inhibit keratinocyte proliferation in normal murine skin. Here, we studied the effects of two TZDs, namely ciglitazone (10 mM) and troglitazone (1 mM), in the same murine model where epidermal hyperproliferation was reproduced by repeated barrier abrogation with tape stripping. Topical treatment with ciglitazone and troglitazone resulted in a marked and significant decrease in epidermal thickness. Furthermore, in all TZD-treated groups, we observed a significant decrease in keratinocyte proliferation using proliferating cell nuclear antigen, 5-bromo-2′-deoxyuridine, and tritiated thymidine incorporation. However, using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, we found no difference in apoptosis between different treatments, emphasizing that it is the antiproliferative role of these activators that accounts for the decrease of epidermal thickness. Finally, using immunohistochemical methods, we determined the effects of ciglitazone on keratinocyte differentiation in this hyperproliferative model. We observed an increased expression of involucrin and filaggrin following ciglitazone treatment, suggesting a pro-differentiating action of TZDs in this model. In summary, topical TZDs significantly reduce epidermal keratinocyte proliferation while promoting differentiation in a murine model of hyperproliferative epidermis. Together, these results suggest that in addition to their metabolic effects currently in use in the treatment of type 2 diabetes, topical TZDs could be considered as potential alternative therapeutic agents in hyperproliferative skin diseases such as psoriasis.

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