Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Tissue Inhibitor Of Metalloproteinase-2 Suppresses Collagen Synthesis Within Keloids
Teruyuki Dohi, MD, Koichi Miyake, MD, PhD, Masayo Aoki, MD, PhD, Rei Ogawa, MD, PhD, Satoshi Akaishi, MD, PhD, Takashi Okada, MD, PhD, Hiko Hyakusoku, MD, PhD.
NIppon Medical School, Tokyo, Japan.

PURPOSE:Keloids are defined as a kind of dermal fibroproliferative disorders result from the accumulation of collagen with chronic inflammation. During ECM remodeling, the balance between matrix metalloproteinases (MMPs) and their inhibitor, the inhibitors of metalloproteinases (TIMPs), is as critical as the proper production of ECM. We previously reported that the expression levels of two collagen types (COL1A2 and COL3A1) are significantly increased in TIMP-2 knockdown keloid fibroblasts. From the evidence currently available, the level of TIMP-2 within keloids is uncertain and the effects of TIMP-2 on keloids had not been previously reported. In this study, we investigate the role of TIMPs and MMPs in the pathogenesis of keloids. Then we also examine the therapeutic potential of TIMP-2 using in vitro and ex vivo cultures of keloid tissue.
METHODS:The expression of TIMPs and MMPs in cultured most inflamed parts of keloid fibroblasts (KFs) and peripheral normal skin fibroblasts (PNFs) in the same individuals, as well as the reactivity of KFs to cyclic mechanical stress (CMS) were analyzed by quantitative real-time RT-PCR (qRT-PCR). To evaluate the effect of treating KFs with recombinant TIMP-2, collagen synthesis (PIP levels) and the expression levels of two collagen types (COL1A2 and COL3A1) were investigated after administration of TIMP-2. Moreover, the effect of TIMP-2 on ex vivo cultures of keloid tissue was also examined by microscopic analysis.
RESULTS:TIMP-2 expression was downregulated in KFs (n=7, p< 0.05), and the reduction in TIMP-2 was exacerbated by CMS (n=7, p< 0.05). Administration of TIMP-2 (200 ng/ml or 300 ng/ml) significantly suppressed collagen synthesis (PIP levels) (n=6, p< 0.05) and expression of Col1A2 and Col3A1 mRNA (n=6, p< 0.05) in KFs. Treatment of TIMP-2 (200 ng/ml) also significantly reduced the skin dermal and collagen bundle thickness in ex vivo cultures of keloid tissue (n=6, p< 0.05).
CONCLUSION:Downregulation of TIMP-2 expression in KFs is a crucial event in the pathogenesis of keloids, and the TIMP-2 would be a candidate gene for their treatment.


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