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Stratifin‐Induced MMP‐1 in Fibroblast is Mediated by c‐Fos and P38 MAPK Activation
Author(s) -
Lam E.,
Tredget E.E.,
Ghahary A.
Publication year - 2008
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/j.1067-1927.2005.130215s.x
Subject(s) - fibroblast , matrix metalloproteinase , extracellular matrix , mapk/erk pathway , wound healing , microbiology and biotechnology , signal transduction , p38 mitogen activated protein kinases , biology , immunology , cell culture , biochemistry , genetics
A delicate balance between synthesis of extracellular matrix (ECM) and degradation by matrix metalloproteinases (MMPs) is a key factor in maintaining the structural integrity of normal skin. Epidermal‐mesenchymal interactions play a critical role in controlling the expression of MMPs during development and healing of skin. Disruption of this interaction increases the frequency of developing fibrotic conditions such as hypertrophic scarring and keloids. In the absence of epithelialization, ECM continues to accumulate until dermal fibroblasts receive signal(s) from epidermal cells to slow down the dynamic process of maturation and remodeling of the healing wound. We have recently demonstrated that keratinocyte releasable stratifin stimulates MMP‐1 expression in dermal fibroblasts. However, the molecular mechanism by which stratifin protein induces MMP‐1 expression in fibroblasts is unknown. Therefore, the purpose of the present study is to identify elements of the signaling pathway mediating stratifin stimulation of fibroblast MMP‐1 expression. We did so by examining the three distinct MAPK pathways: ERK1/2, JNK, and p38 as well as the expression of the main components of the AP‐1 dimers, c‐Jun and c‐Fos, which are mediated by distinct MAPK pathways. Our data shows that treatment of fibroblasts with stratifin resulted in rapid and transient up‐regulation of c‐jun and c‐fos mRNA levels. Furthermore, we show that stratifin activates fibroblast MMP‐1 expression at the mRNA and protein levels and this is mediated by p38 MAP kinase. Subsequent cDNA microarray analysis of fibroblasts treated with stratifin show an increase in a ternary complex factor, Sap‐1. In conclusion, our results describes the mechanism by which stratifin activates MMP‐1 in fibroblast, and demonstrates that p38 MAP kinase is an important regulator of MMP‐1 gene expression involved in epidermal‐mesenchymal interactions in wound remodeling. Acknowledgment: This work was supported by the Canadian Institute of Health Research (CIHR).