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TRANSIENT RECEPTOR POTENTIAL C3 PLAY AN IMPORTANT ROLE IN THE FORMATION OF HYPERTROPHIC SCAR AS A MECHANICAL TRANSDUCER
Presenter: Hisako Ishise, MD
Co-Authors: Kawai K; Larson BJ; Nishimoto S; Kakibuchi M
Hyogo College of Medicine

Introduction: Hypertrophic scarring is the result of an exaggerated wound healing response that results in the over deposition of collagen. This process tends to occur in areas undergoing repetitive mechanical stretch stimulations, such as at the elbows and knees. However, the link between mechanical stretching and collagen deposition is still unknown. Calcium channels mediate calcium influx into cells, and it is thought that mechanical stretch forces may lead to an up-regulation of ion channels. Recently, an ion channel group called Transient-Receptor-Potential (TRP) has been identified as a possible mechanical transducer. We investigated the role of the TRPC3 homologue in the pathogenesis of hypertrophic scarring.

Methods: The expression levels of TRPC homologues in human hypertrophic scar samples were analyzed via immunohistochemistry. Next, TRPC3 overexpressing fibroblasts (NIH3T3) were prepared through gene transfection. Then, both normal and TRPC3 overexpressing fibroblasts were seeded in silicon chambers and exposed to repetitive mechanical stretch forces. The expression levels of various genes related to hypertrophic scar formation, such as collagen, IL6 and TGF≤-beta were examined using qRT-PCR. The cell signaling pathways were analyzed using Western blotting.

Results: TRPC3 expression levels were elevated in human hypertrophic scars, as evidenced by immunohistochemistry. TRPC3 over-expressing fibroblasts also had elevated levels of IL-6, when compared to normal fibroblast. Western blot analysis demonstrated that mechanical stretching induced NFkB expression in TRPC3 over-expressing fibroblasts.

Conclusion: IL-6 is known to promote collagen deposition, and fibroblasts from keloid tissue have higher levels of IL-6, when compared to normal fibroblasts. The IL-6 promoter has an NFkB binding element and the expression of IL-6 is partly regulated by the activity of the MAPK-NFkB pathway. NFkB activation is mediated by cytoplasmic calcium, which in turn is mediated by the TRPC3 channel in response to mechanical stretching. It is suggested that TRPC3 plays an important role in the pathogenesis of hypertrophic scarring.


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