The Effect of Suppressing Discoidin Domain Receptor Expression on Keloid Formation and Proliferation
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The reason why this occurs may be because during morphogenesis the tissue and organs build up and the characteristic fetal skin has scarless phenotype in which the DDR1, as sensors for ECM, is highly expressed to facilitate collagen modulation and organization. As the fetal scar healing period progresses, the miniature of an adult form resolves and the refined modulation of collagen organization gradually reaches homeostasis, and as a result, the expression of DDR1 is gradually decreased. Once the skin is wounded, this tissue building machinery is dramatically reawakened and the repair becomes a recapitulation of morphogenesis. As a result, ECM forms and the expression of DDR1 is greatly increased.15 However, this process is different in keloid formation, hence the variation in findings.
Additionally, it was observed that the viability of keloid dermal fibroblasts significantly decreased after treatment with DDR1-ASODN. Ongusaha et al16 also reported that DDR1 activated the mitogen-activated protein kinase (MAPK) cascade. Additionally, Ongusaha et al suggest that DDR1 can function as a survival effect directly. Their data support our finding that blocking the expression of DDR1 is associated with decreased cell viability.
Furthermore, according to the manual of Lipofectamine™ 2000 transfection reagent (Gibco-BRL Life Technologies, Invitrogen, Gaithersburg, MD), transfection efficiency is only 48% in primary human fibroblasts. The manual suggests that only half of keloid dermal fibroblasts can successively interrupt DDR1 expression in the culture plate. The results of the present study further demonstrate that some DDR1 can exert regulatory effect on collagen structure. These findings reveal that DDR1 can sense the quality of collagen, activate the signals, and regulate cellular behavior thus modulating collagen proliferation, production, and organization.
The distribution of DDR2 is not as widely dispersed as that of DDR1. In our experiments, the expression of DDR2 remained fairly constant between keloid fibroblasts and normal dermal fibroblasts (data not shown). The exact role of DDR2 will require further investigation.
Another issue that needs to be studied further is how these in-vitro findings correlate with in-vivo results. Additionally, it needs to be addressed why a difference exists in healing at two different sites in a person who suffers from keloid formation at a given anatomical location. A follow-up study using different skin samples—normal and keloid tissue from the same subjects—will shed some light on the differences in fibroblast heterogeneity. We believe that this study will provide baseline data that can be used in future clinical trials and also shed some light on other unresolved issues.
This study has shown for the first time that keloids can be inhibited by targeting DDR1 signaling using a DDR1-ASODN treatment. The effect of DDR1-ASODN treatment on long-term results and animal model remains to be investigated. However, this study demonstrates a close relationship between collagen and DDRs in keloid dermal fibroblasts and is likely to open newer avenues for further investigations on wound healing, which may prove to be useful in the future.
The authors would like to thank Dr. C-Y Ni and Y-H Cao for their technical assistance on this project.
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