title: Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation.
abstract: Wound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue. Hypertrophic scar contracture is considered to be a pathologic and exaggerated wound healing response that is known to be triggered by repetitive mechanical forces. We now show that Transient Receptor Potential (TRP) C3 regulates the expression of fibronectin, a key regulatory molecule involved in the wound healing process, in response to mechanical strain via the NFkB pathway. TRPC3 is highly expressed in human hypertrophic scar tissue and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. TRPC3 overexpressing fibroblasts subjected to repetitive stretching forces showed robust expression levels of fibronectin. Furthermore, mechanical stretching of TRPC3 overexpressing fibroblasts induced the activation of nuclear factor-kappa B (NFκB), a regulator fibronectin expression, which was able to be attenuated by pharmacologic blockade of either TRPC3 or NFκB. Finally, transplantation of TRPC3 overexpressing fibroblasts into mice promoted wound contraction and increased fibronectin levels in vivo. These observations demonstrate that mechanical stretching drives fibronectin expression via the TRPC3-NFkB axis, leading to intractable wound contracture. This model explains how mechanical strain on cutaneous wounds might contribute to pathologic scarring.
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Ishise
authors.affiliation: Department of Anesthesiology, Pain &Perioperative Medicine Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305 USA.
authors.forename: Barrett
authors.initials: B
authors.lastname: Larson
authors.affiliation: Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Soh
authors.initials: S
authors.lastname: Nishimoto
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, 2-2-C11, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Tateki
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, 2-2-C11, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Department of Plastic Surgery, Osaka University Graduate School of Medicine, 2-2-C11, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kanazawa
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sotsuka
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kakibuchi
authors.affiliation: Department of Plastic Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kawai
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003286:Contracture / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020405:Dermis / Q000166:cytology; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology / Q000637:transplantation; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D005353:Fibronectins; D016328:NF-kappa B; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel