title: The role of R-spondin2 in keratinocyte proliferation and epidermal thickening in keloid scarring.
abstract: Keloids are found only in humans and the underlying biochemical mechanisms of their pathogenesis remain unknown. R-spondins (Rspos) are a relatively new group of secreted proteins known to be Wnt/β-catenin signaling agonists, but their role in keloids has yet to be elucidated. We investigated the expression levels of R-spondin2 (Rspo2) in cell lysates and conditioned media of monocultures and co-cultures of fibroblasts and keratinocytes derived from keloids and normal skin. In this study we found increased protein expression and secretion of Rspo2 in respective monocultures of keloid fibroblasts and keratinocytes when compared with their normal counterparts. Double-chamber co-culture experiments implicated the role of keloid keratinocytes (KKs) in the induction of Rspo2 secretion from fibroblasts because of epithelial-mesenchymal interactions. Addition of recombinant human Rspo2 in culture increased the proliferation of keratinocytes and it acted synergistically with Wnt3a through the canonical Wnt/β-catenin pathway. Overexpression of Rspo2 in normal fibroblasts brought about thicker epidermis when compared with control fibroblasts in a skin organotypic culture model. This observation coincides with the hyperproliferative phenotype of thickened epidermis seen in keloids. Taken together, the results suggest the possible double paracrine action of KKs in inducing higher expression of Rspo2 in fibroblasts that promotes keratinocyte proliferation and epidermal thickening.
authors.affiliation: Skin Bank Unit, Singapore General Hospital, Singapore. alvin.chua.w.c@sgh.com.sg
authors.forename: Alvin W C
authors.initials: AW
authors.lastname: Chua
authors.forename: Dongrui
authors.initials: D
authors.lastname: Ma
authors.forename: Shu U
authors.initials: SU
authors.lastname: Gan
authors.forename: Zhenying
authors.initials: Z
authors.lastname: Fu
authors.forename: Hwan C
authors.initials: HC
authors.lastname: Han
authors.forename: Colin
authors.initials: C
authors.lastname: Song
authors.forename: Kanaga
authors.initials: K
authors.lastname: Sabapathy
authors.forename: Toan T
authors.initials: TT
authors.lastname: Phan
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004817:Epidermis / Q000473:pathology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007627:Keloid / Q000473:pathology* / Q000503:physiopathology; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D019699:Thrombospondins / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000502:physiology; D000098907:R-Spondins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D019699:Thrombospondins; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin; C503243:RSPO1 protein, human; D000098907:R-Spondins; C557408:Rspo2 protein, human; C555510:WNT3A protein, human