Open AccessPPARδ promotes wound healing by up‐regulating TGF‐β1‐dependent or ‐independent expression of extracellular matrix proteins
Author(s) -
Ham Sun Ah,
Kim Hyo Jung,
Kim Hyun Joon,
Kang Eun Sil,
Eun So Young,
Kim Gil Hyeong,
Park Myung Hyun,
Woo Im Sun,
Kim Hye Jung,
Chang Ki Churl,
Lee Jae Heun,
Seo Han Geuk
Publication year - 2010
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00816.x
Subject(s) - extracellular matrix , microbiology and biotechnology , fibronectin , wound healing , biology , receptor , peroxisome proliferator activated receptor , signal transduction , peroxisome proliferator activated receptor delta , transforming growth factor , nuclear receptor , transcription factor , biochemistry , immunology , gene
Although the peroxisome proliferator‐activated receptor (PPAR) δ has been implicated in the wound healing process, its exact role and mechanism of action have not been fully elucidated. Our previous findings showed that PPARδ induces the expression of the transforming growth factor (TGF)‐β1, which has been implicated in the deposit of extracellular matrix proteins. Here, we demonstrate that administration of GW501516, a specific PPARδ ligand, significantly promoted wound closure in the experimental mouse and had a profound effect on the expression of collagen types I and III, alpha‐smooth muscle actin, pSmad3 and TGF‐β1, which play a pivotal role in wound healing processes. Activation of PPARδ increased migration of human epidermal keratinocytes and dermal fibroblasts in in vitro scrape‐wounding assays. Addition of a specific ALK5 receptor inhibitor SB431542 significantly suppressed GW501516‐induced migration of human keratinocytes and fibroblasts. In these cells, activated PPARδ also induced the expression of collagen types I and III and fibronectin in a TGF‐β1‐dependent or ‐independent manner. The effect of PPARδ on the expression of type III collagen was dually regulated by the direct binding of PPARδ and Smad3 to a direct repeat‐1 site and a Smad‐binding element, respectively, of the type III gene promoter. Taken together, these results demonstrated that PPARδ plays an important role in skin wound healing in vivo and that it functions by accelerating extracellular matrix‐mediated cellular interactions in a process mediated by the TGF‐β1/Smad3 signaling‐dependent or ‐ independent pathway.