title: RGD-containing fibrillin-1 fragments upregulate matrix metalloproteinase expression in cell culture: a potential factor in the pathogenesis of the Marfan syndrome.
abstract: The Marfan syndrome (MFS), a relatively common autosomal dominant disorder of connective tissue, is caused by mutations in the gene for fibrillin-1 (FBN1). Fibrillin-1 is the main component of the 10- to 12-nm microfibrils that together with elastin form elastic fibers found in tissues such as the aortic media. Recently, FBN1 mutations have been shown to increase the susceptibility of fibrillin-1 to proteolysis in vitro, and other findings suggest that up-regulation of matrix metalloproteinases (MMP), as well as fragmentation of microfibrils, could play a role in the pathogenesis of MFS. In the present work, we have investigated the influence of fibrillin-1 fragments on the expression of MMP-1, MMP-2, and MMP-3 in a cell culture system. Cultured human dermal fibroblasts were incubated with several different recombinant fibrillin-1 fragments. The expression level of MMP-1, MMP-2, and MMP-3, was determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and the concentration of the corresponding proteins was estimated by quantitative Western blotting. Our results establish that treatment of cultured human dermal fibroblasts with recombinant fibrillin-1 fragments containing the arginine-glycine-aspartic acid (RGD) integrin-binding motif of fibrillin-1 induces up-regulation of MMP-1 and MMP-3. A similar effect was seen upon stimulation with a synthetic RGD peptide. The expression of MMP-2 was not influenced by treatment. Our results suggest the possibility that fibrillin fragments could themselves have pathogenic effects by leading to up-regulation of MMPs, which in turn may be involved in the progressive breakdown of microfibrils thought to play a role in MFS.
authors.affiliation: Institute of Medical Genetics, Charité University Hospital, Humboldt University Berlin, Augustenburger Platz 1, Berlin 13353, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Booms
authors.forename: Reinhard
authors.initials: R
authors.lastname: Pregla
authors.forename: Andreas
authors.initials: A
authors.lastname: Ney
authors.forename: Frank
authors.initials: F
authors.lastname: Barthel
authors.forename: Dieter P
authors.initials: DP
authors.lastname: Reinhardt
authors.forename: Angelika
authors.initials: A
authors.lastname: Pletschacher
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
mesh_terms: D004790:Enzyme Induction; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008382:Marfan Syndrome / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009842:Oligopeptides / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D020539:Sequence Analysis, Protein; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D020782:Matrix Metalloproteinases; D008840:Microfilament Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; C000605722:FBN1 protein, human; D054392:Adipokines; C047981:arginyl-glycyl-aspartic acid