title: Synthetic ligands of the elastin receptor induce elastogenesis in human dermal fibroblasts via activation of their IGF-1 receptors.
abstract: BACKGROUND
  We have previously reported that a mixture of peptides obtained after chemical or enzymatic degradation of bovine elastin, induced new elastogenesis in human skin.
  
  
  OBJECTIVE
  Now, we investigated the elastogenic potential of synthetic peptides mimicking the elastin-derived, VGVAPG sequence, IGVAPG sequence that we found in the rice bran, and a similar peptide, VGVTAG that we identified in the IGF-1-binding protein-1 (IGFBP-1).
  
  
  RESULTS
  We now demonstrate that treatment with each of these xGVxxG peptides (recognizable by the anti-elastin antibody), up-regulated the levels of elastin-encoding mRNA, tropoelastin protein, and the deposition of new elastic fibers in cultures of human dermal fibroblasts and in cultured explants of human skin. Importantly, we found that such induction of new elastogenesis may involve two parallel signaling pathways triggered after activation of IGF-1 receptor. In the first one, the xGVxxG peptides interact with the cell surface elastin receptor, thereby causing the downstream activation of the c-Src kinase and a consequent cross-activation of the adjacent IGF-1R, even in the absence of its principal ligand. In the second pathway their hydrophobic association with the N-terminal domain (VGVTAG) of the serum-derived IGFBP-1 induces conformational changes of this IGF-1 chaperone allowing for the release of its cargo and a consequent ligand-specific phosphorylation of IGF-1R.
  
  
  CONCLUSIONS
  We present a novel, clinically relevant mechanism in which products of partial degradation of dermal elastin may stimulate production of new elastic fibers by dermal fibroblasts. Our findings particularly encourage the use of biologically safe synthetic xGVxxG peptides for regeneration of the injured or aged human skin.
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children, ON, Canada; Institute of Medical Science, University of Toronto, ON, Canada.
authors.forename: Nour
authors.initials: N
authors.lastname: Qa'aty
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children, ON, Canada.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children, ON, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wang
authors.affiliation: Human Matrix Sciences, LLC, Visalia, CA, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Mitts
authors.affiliation: Physiology & Experimental Medicine Program, Hospital for Sick Children, ON, Canada; Institute of Medical Science, University of Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada. Electronic address: alek.hinek@sickkids.ca.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Hinek
mesh_terms: D000328:Adult; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D004549:Elastin / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D008024:Ligands; D008875:Middle Aged; D018832:Molecular Chaperones / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology / Q000378:metabolism; D012879:Skin Physiological Phenomena; D046509:Tissue Culture Techniques; D014333:Tropoelastin / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D008024:Ligands; D018832:Molecular Chaperones; D009842:Oligopeptides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014333:Tropoelastin; C054901:elastin-binding proteins; D004549:Elastin; D017526:Receptor, IGF Type 1; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: Elastin receptor; Elastin-like peptides; Elastogenesis; Human skin regeneration; IGF-1 receptor