Tretinoin reverses upregulation of matrix metalloproteinase-13 in human keloid-derived fibroblasts.
Keloids are skin abnormalities that are characterized by excessive deposition of collagen bundles in the dermis. Patients with keloids complain not only about their cosmetic appearance, but also about continuous itching and/or tenderness associated with chronic inflammation. Degradation of extracellular matrix (ECM) may be upregulated, associated with the expansion of keloids into circumferential skin, and high metabolic activity of keloid tissues may be due to increased matrix metalloproteinase (MMP) activity. Based on these hypotheses, we examined differences in expression of MMP-1, MMP-8, and MMP-13 between keloid-derived and normal dermal fibroblasts. Since retinoids are potent inhibitors of MMPs in the treatment of photoaged skin and cancers, we also examined whether or not tretinoin affects MMP expression of keloid-derived fibroblasts. The results of real-time polymerase chain reaction and ELISA demonstrated significant upregulation of MMP-13 and significant downregulation of MMP-1 and MMP-8 in keloid-derived fibroblasts, at both mRNA and protein levels. MMP-1 mRNA expression in the control group was significantly upregulated after the addition of tretinoin, whereas no significant change was observed in the keloid group. MMP-8 mRNA expression in the control group was significantly upregulated by tretinoin, with the peak at 12 h, while no significant change was observed in the keloid-derived fibroblasts. In contrast, the remarkably elevated MMP-13 mRNA expression in the keloid group was significantly suppressed, with the peak suppression at 12 h after addition of tretinoin, while MMP-13 mRNA expression in the control group was not significantly changed. The decrease in MMP-1 and MMP-8 may contribute to accumulation of type I and type III collagen in keloid tissues, and this mechanism may be modulated by molecular interaction with MMP-13. Tretinoin appeared to reverse the abnormal expression profile of MMPs in keloid-derived fibroblasts, such as markedly elevated expression of MMP-13, partly through inactivation of AP-1 pathway. The present results suggest that tretinoin may be clinically useful to improve the chronic inflammation seen in keloids and prevent expansion of keloid tissues into circumferential normal skin.
Uchida
Gentaro
G
Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Yoshimura
Kotaro
K
Kitano
Yukie
Y
Okazaki
Mutsumi
M
Harii
Kiyonori
K
D000328:Adult; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D003470:Culture Media / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007627:Keloid / Q000201:enzymology* / Q000473:pathology; D007641:Keratolytic Agents / Q000494:pharmacology*; D008297:Male; D020781:Matrix Metalloproteinase 1; D053509:Matrix Metalloproteinase 13; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000201:enzymology / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D003470:Culture Media; D007641:Keratolytic Agents; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D014212:Tretinoin; D010749:Phosphoprotein Phosphatases; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020784:Matrix Metalloproteinase 8; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1