title: Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome.
abstract: OBJECTIVE
  Chronic inflammation of the lacrimal gland results in changes in the composition of the extracellular matrix (ECM), which is believed to compromise tissue repair. We hypothesized that increased production/activity of matrix metalloproteinases (MMPs), especially MMP-2 and -9, in inflamed lacrimal glands modifies the ECM environment, therefore disrupting tissue repair.
  
  
  METHODS
  The lacrimal glands from female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for histology, immunohistochemistry, zymography, Western blotting, and RNA analyses. In another study, MRL/lpr mice were treated for 5 weeks with a selective MMP2/9 inhibitor peptide or a control peptide. At the end of treatment, the lacrimal glands were excised and the tissue was processed as described above.
  
  
  RESULTS
  There was a 2.5- and 2.7-fold increase in MMP2 gene expression levels in MRL/lpr and NOD mice, respectively. Matrix metalloproteinase 2 and 9 enzymatic activities and protein expression levels were significantly upregulated in the lacrimal glands of MRL/lpr and NOD mice compared to controls. Treatment with the MMP2/9 inhibitor resulted in decreased activity of MMP-2 and -9 both in vitro and in vivo. Importantly, MMP2/9 inhibitor treatment of MRL/lpr mice improved aqueous tear production and resulted in reduced number and size of lymphocytic foci in diseased lacrimal glands.
  
  
  CONCLUSIONS
  We conclude that MMP2/9 expression and activity are elevated in lacrimal glands of two murine models of Sjögren's syndrome, suggesting that manipulation of MMP2/9 activity might be a potential therapeutic target in chronically inflamed lacrimal glands.
authors.affiliation: Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States.
authors.forename: Hema S
authors.initials: HS
authors.lastname: Aluri
authors.affiliation: Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Kublin
authors.affiliation: Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States.
authors.forename: Suharika
authors.initials: S
authors.lastname: Thotakura
authors.affiliation: Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States.
authors.forename: Helene
authors.initials: H
authors.lastname: Armaos
authors.affiliation: Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States.
authors.forename: Mahta
authors.initials: M
authors.lastname: Samizadeh
authors.affiliation: Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States.
authors.forename: Dillon
authors.initials: D
authors.lastname: Hawley
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States.
authors.forename: William M
authors.initials: WM
authors.lastname: Thomas
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University, Boston, Massachusetts, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Leavis
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States.
authors.forename: Helen P
authors.initials: HP
authors.lastname: Makarenkova
authors.affiliation: Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States.
authors.forename: Driss
authors.initials: D
authors.lastname: Zoukhri
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007765:Lacrimal Apparatus / Q000201:enzymology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012859:Sjogren's Syndrome / Q000201:enzymology / Q000235:genetics*; D013666:Tears / Q000201:enzymology*
chemical_list: D012313:RNA; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse