Conformational Dependence of Collagenase (Matrix Metalloproteinase-1) Up-regulation by Elastin Peptides in Cultured Fibroblasts

Abstract : We have established that treatment of cultured human skin fibroblasts with tropoelastin or with heterogenic peptides, obtained after organo-alkaline or leukocyte elastase hydrolysis of insoluble elastin, induces a high expression of pro-collagenase-1 (pro-matrix metalloproteinase-1 (pro-MMP-1)). The identical effect was achieved after stimulation with a VGVAPG synthetic peptide, reflecting the elastin-derived domain known to bind to the 67-kDa elastin-binding protein. This clearly indicated involvement of this receptor in the described phenomenon. This notion was further reinforced by the fact that elastin peptides-dependent MMP-1 up-regulation has not been demonstrated in cultures preincubated with 1 mm lactose, which causes shedding of the elastin-binding protein and with pertussis toxin, which blocks the elastin-binding protein-dependent signaling pathway involving G protein, phospholipase C, and protein kinase C. Moreover, we demonstrated that diverse peptides maintaining GXXPG sequences can also induce similar cellular effects as a "principal" VGVAPG ligand of the elastin receptor. Results of our biophysical studies suggest that this peculiar consensus sequence stabilizes a type VIII beta-turn in several similar, but not identical, peptides that maintain a sufficient conformation to be recognized by the elastin receptor. We have also established that GXXPG elastin-derived peptides, in addition to pro-MMP-1, cause up-regulation of pro-matrix metalloproteinase-3 (pro-stromelysin 1). Furthermore, we found that the presence of plasmin in the culture medium activated these MMP proenzymes, leading to a consequent degradation of collagen substrate. Our results may be, therefore, relevant to pathobiology of inflammation, in which elastin-derived peptides bearing the GXXPG conformation (created after leukocyte-dependent proteolysis) bind to the elastin receptor of local fibroblasts and trigger signals leading to expression and activation of MMP-1 and MMP-3, which in turn exacerbate local connective tissue damage.
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Submitted on : Wednesday, October 23, 2019 - 1:37:38 PM
Last modification on : Friday, November 8, 2019 - 1:40:54 AM

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Bertrand Brassart, Patrick Fuchs, Eric Huet, Alain Alix, Jean Wallach, et al.. Conformational Dependence of Collagenase (Matrix Metalloproteinase-1) Up-regulation by Elastin Peptides in Cultured Fibroblasts. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2001, 276 (7), pp.5222-5227. ⟨10.1074/jbc.M003642200⟩. ⟨hal-02328935⟩

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