title: Activation of latent transforming growth factor beta 1 and inhibition of matrix metalloprotease activity by a thrombospondin-like tripeptide linked to elaidic acid.
abstract: Impaired wound healing and skin aging are characterized by neutral protease-mediated destruction of matrix macromolecules associated with disturbance in tissue repair. We synthesized a fatty acyl-peptide derivative at aims to simultaneously activate latent TGF-beta through its peptide domain, KFK, and inhibit MMPs through its lipophilic moiety, elaidic acid. Elaidyl-KFK as well as KFK were shown to activate LAP-TGF-beta both in vitro, using a solid phase assay with immobilized LAP-TGF-beta, and ex vivo using human dermal fibroblasts cultures. In both assays, as much as up to 10% of LAP-TGF-beta added could be recovered as active form. KQK, KQFK as well as their lipopeptide counterparts were inactive. Elaidyl-KFK-mediated LAP-TGF-beta activation led to up-regulation of collagen and TIMP-1 production and down regulation of PMA-induced MMP-1 expression in fibroblasts cultures. Those effects could be suppressed by supplementing cell culture medium with blocking TGF-beta antibody. Elaidyl-KFK inhibited MMP-2, MMP-9, MMP-3, MMP-1, in vitro with IC(50) equal to 1.2, 1.0, 0.24 and 8.9 microM, respectively. Its ex vivo inhibitory capacity, as assessed using skin tissue sections, towards the elastin-degrading capacity of MMP-9 was even more pronounced. At a 1 microM concentration, the lipopeptide decreased by up to 80% enzyme activity. Thus, "Lipospondin," i.e. elaidyl-KFK might be considered as a promising model compound to prevent age-associated dermal alterations.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, UMR 6198 CNRS, IFR-53 "Biomolecules", Faculty of Medicine, University of Reims Champagne-Ardenne, 51 Rue Cognacq Jay, 51095 Reims cedex, France.
authors.forename: Jean-Hubert
authors.initials: JH
authors.lastname: Cauchard
authors.forename: Alix
authors.initials: A
authors.lastname: Berton
authors.forename: Gaston
authors.initials: G
authors.lastname: Godeau
authors.forename: William
authors.initials: W
authors.lastname: Hornebeck
authors.forename: Georges
authors.initials: G
authors.lastname: Bellon
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D019301:Oleic Acid / Q000737:chemistry*; D009829:Oleic Acids; D009842:Oligopeptides / Q000494:pharmacology*; D019699:Thrombospondins / Q000737:chemistry* / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D009829:Oleic Acids; D009842:Oligopeptides; C508960:TGFB1 protein, human; D019699:Thrombospondins; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019301:Oleic Acid; C011459:elaidic acid; C079731:lysyl-phenylalanyl-lysine; D008666:Metalloendopeptidases