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

Marianne Demerjian, Mao Qiang Man, Eung Ho Choi, Barbara E. Brown, Debra Crumrine, Sandra Chang, Theodora Mauro, Peter M. Elias, Kenneth R. Feingold

Research output: Contribution to journalArticle

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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 (10mM) 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.

Original languageEnglish
Pages (from-to)154-160
Number of pages7
JournalExperimental Dermatology
Volume15
Issue number3
DOIs
Publication statusPublished - 2006 Mar 1

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Thiazolidinediones
Peroxisome Proliferator-Activated Receptors
Homeostasis
troglitazone
Keratinocytes
Skin
DNA Nucleotidylexotransferase
Proliferating Cell Nuclear Antigen
Bromodeoxyuridine
Medical problems
Psoriasis
Skin Diseases
Epidermis
Liver
Thymidine
Tapes
Labeling
Type 2 Diabetes Mellitus
Hyperplasia
Assays

All Science Journal Classification (ASJC) codes

  • Dermatology

Cite this

Demerjian, Marianne ; Man, Mao Qiang ; Choi, Eung Ho ; Brown, Barbara E. ; Crumrine, Debra ; Chang, Sandra ; Mauro, Theodora ; Elias, Peter M. ; Feingold, Kenneth R. / Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-γ, normalizes epidermal homeostasis in a murine hyperproliferative disease model. In: Experimental Dermatology. 2006 ; Vol. 15, No. 3. pp. 154-160.
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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 (10mM) 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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Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-γ, normalizes epidermal homeostasis in a murine hyperproliferative disease model. / Demerjian, Marianne; Man, Mao Qiang; Choi, Eung Ho; Brown, Barbara E.; Crumrine, Debra; Chang, Sandra; Mauro, Theodora; Elias, Peter M.; Feingold, Kenneth R.

In: Experimental Dermatology, Vol. 15, No. 3, 01.03.2006, p. 154-160.

Research output: Contribution to journalArticle

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T1 - Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-γ, normalizes epidermal homeostasis in a murine hyperproliferative disease model

AU - Demerjian, Marianne

AU - Man, Mao Qiang

AU - Choi, Eung Ho

AU - Brown, Barbara E.

AU - Crumrine, Debra

AU - Chang, Sandra

AU - Mauro, Theodora

AU - Elias, Peter M.

AU - Feingold, Kenneth R.

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