Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-γ, normalizes epidermal homeostasis in a murine hyperproliferative disease model
Topical treatment with thiazolidinediones, activators of peroxisome proliferator-activated receptor-γ, normalizes epidermal homeostasis in a murine hyperproliferative disease model
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DOI：
10.1111/j.1600-0625.2006.00402.x
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发表时间：
2006-03-01
影响因子：
3.6
通讯作者：
Feingold, KR
中科院分区：
文献类型：
--
作者：
Demerjian, M;Man, MQ;Feingold, KR
在复制几种常见皮肤疾病的一些异常的表皮增生的小鼠模型中，我们先前证明了过氧化物酶体增殖物激活受体（PPAR）α、PPAR β/δ和肝X受体激活剂的抗增殖和促分化作用。与其他亚型的过氧化物酶体增殖物激活物，噻唑烷二酮类（TZDs），一个家庭的过氧化物酶体增殖物激活物激活物γ配体，不抑制正常小鼠皮肤角质形成细胞增殖。在这里，我们研究了两个TZD，即环格列酮（10 mM）和曲格列酮（1 mM），在同一个小鼠模型，其中表皮过度增殖再现的反复屏障废除与磁带剥离的影响。用环格列酮和曲格列酮局部治疗导致表皮厚度显著降低。此外，在所有TZD处理组中，我们观察到使用增殖细胞核抗原、5-溴-2 '-脱氧尿苷和氚化胸苷掺入的角质形成细胞增殖显著降低。然而，使用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法，我们发现不同治疗之间的细胞凋亡没有差异，强调这是这些激活剂的抗增殖作用，占表皮厚度的减少。最后，使用免疫组织化学方法，我们确定了环格列酮对角质形成细胞分化在这个过度增殖模型的影响。我们观察到ciglitazone治疗后外皮蛋白和聚丝蛋白的表达增加，表明TZDs在该模型中具有促分化作用。总之，在过度增殖表皮的鼠模型中，局部TZD显著降低表皮角质形成细胞增殖，同时促进分化。总之，这些结果表明，除了目前用于治疗2型糖尿病的代谢作用外，局部TZD可被视为过度增殖性皮肤病（如银屑病）的潜在替代治疗药物。
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)alpha, PPAR beta/delta, and liver X receptor activators. Unlike other subgroups of PPAR activators, thiazolidinediones (TZDs), a family of PPAR gamma 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.