title: Matrix metalloproteinase (MMP)-9 type IV collagenase/gelatinase implicated in the pathogenesis of Sjögren's syndrome.
abstract: Type IV collagenases/gelatinases (matrix metalloproteinases MMP-2 and MMP-9) in labial salivary glands (LSG) and saliva in Sjögren's syndrome (SS) and healthy controls were studied. Zymograms and Western blots disclosed that SS saliva contained 92/82 kD MMP-9/type IV collagenase duplex. Specific activity measurement disclosed 53.1+/-9.8 U/mg protein MMP-9 in SS compared to 16.5+/-2.6 U/mg in healthy controls (p=0.01). MMP-2 did not differ between SS and controls. In SS salivary glands, MMP-2 and MMP-9 were also expressed, in addition to stromal fibroblasts and occasional infiltrating neutrophils, respectively, in acinar end piece cells. In addition, an effective proMMP-9 activator, human trypsin-2 (also known as tumor-associated trypsin-2 or TAT-2), was found in acinar end piece cells and in saliva. Interestingly, proteolytically processed MMP-9 was found in saliva (vide supra), and in vivo activated MMP-9 was significantly higher in SS than in controls (p=0.002). LSGs, particularly in SS, were characterized ultrastructurally by areas containing small cytoplasmic vesicles in the basal parts of the epithelial cells associated with areas of disordered and thickened basal lamina. Based on our results, we conclude here that SS saliva contains increased concentrations of MMP-9, which is of glandular origin in part. Pro MMP-9 is to a large extent proteolytically activated. This is probably mediated by the most potent pro MMP-9 activator found in vivo thus far, namely trypsin-2. Therefore, the MMP 9/trypsin-2 cascade may be responsible for the increased remodelling and/or structural destruction of the basement membrane scaffolding in salivary glands in SS. Due to the role of basal lamina as an important molecular sieve and extracellular matrix-cell signal, these pathological changes may contribute to the pathogenesis of the syndrome.
authors.affiliation: Department of Anatomy, University of Helsinki, Finland.
authors.forename: Y T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: S
authors.initials: S
authors.lastname: Halinen
authors.forename: R
authors.initials: R
authors.lastname: Hanemaaijer
authors.forename: T
authors.initials: T
authors.lastname: Sorsa
authors.forename: J
authors.initials: J
authors.lastname: Hietanen
authors.forename: A
authors.initials: A
authors.lastname: Ceponis
authors.forename: J W
authors.initials: JW
authors.lastname: Xu
authors.forename: R
authors.initials: R
authors.lastname: Manthorpe
authors.forename: J
authors.initials: J
authors.lastname: Whittington
authors.forename: A
authors.initials: A
authors.lastname: Larsson
authors.forename: T
authors.initials: T
authors.lastname: Salo
authors.forename: L
authors.initials: L
authors.lastname: Kjeldsen
authors.forename: U H
authors.initials: UH
authors.lastname: Stenman
authors.forename: A Z
authors.initials: AZ
authors.lastname: Eisen
mesh_terms: D015153:Blotting, Western; D017364:Collagenases / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism; D008854:Microscopy, Electron; D016133:Polymerase Chain Reaction; D012469:Salivary Glands / Q000201:enzymology / Q000648:ultrastructure; D012859:Sjogren's Syndrome / Q000201:enzymology*
chemical_list: D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9