title: Increased degradation of extracellular matrix structures of lacrimal glands implicated in the pathogenesis of Sjögren's syndrome.
abstract: Lacrimal glands (LGs) of male non-obese diabetic (NOD) mice display many features of human LGs in patients afflicted with the autoimmune disease Sjögren's syndrome (SS), including the loss of secretory functions and a lymphocytic infiltration into the glands by 4 months of age. So far, research has mainly focused on the intracellular events that are involved in initiating LG dysfunction; however, the impact of SS on extracellular matrix (ECM) structures of the diseased LGs has not yet been determined. In this study we identified and compared LG ECM formation and integrity of age-matched male healthy (BALB/c) and diseased (NOD) mice. LG tissues were examined using routine histological, biochemical, immunohistochemical and gene expression analysis. Multiphoton imaging and second-harmonic generation (SHG) microscopy permitted the non-invasive analysis of major LG ECM structures including collagen- and elastin-containing fibers. Biochemical testing demonstrated a significant loss of collagen, glycosaminoglycans and desmosine in NOD LGs when compared to healthy BALB/c LGs. Immunohistochemical staining and gene expression analysis confirmed this disease-related alteration of LG ECM structures. Furthermore, laser-induced autofluorescence and SHG microscopy revealed dramatic changes in the structural organization of most collagenous and elastic fibers of the diseased LG tissues that were more pronounced than those displayed by histological analysis. Our results clearly show an enhanced degradation of ECM proteins accompanied by the severe disorganization and deformation of ECM structures of diseased LG tissues. These new insights into the involvement of ECM degradation in SS may lead to novel therapies for patients suffering from dry eye disease.
authors: Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, Los Angeles/CA 90095-1760, USA. kschenkelayland@mednet.ucla.edu
authors: Katja
authors: K
authors: Schenke-Layland
authors: Jiansong
authors: J
authors: Xie
authors: Ekaterini
authors: E
authors: Angelis
authors: Barry
authors: B
authors: Starcher
authors: Kaijin
authors: K
authors: Wu
authors: Iris
authors: I
authors: Riemann
authors: W Robb
authors: WR
authors: MacLellan
authors: Sarah F
authors: SF
authors: Hamm-Alvarez
mesh_terms: D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003895:Desmosine / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007765:Lacrimal Apparatus / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D020411:Oligonucleotide Array Sequence Analysis; D012859:Sjogren's Syndrome / Q000473:pathology* / Q000503:physiopathology
chemical_list: D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D003895:Desmosine; D003094:Collagen
references: Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3293-302
references: 16877394
references: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12485-90
references: 11606713
references: J Clin Invest. 2005 Sep;115(9):2363-72
references: 16138190
references: Z Zellforsch Mikrosk Anat. 1973 Nov 15;144(4):453-66
references: 4793164
references: J Biol Chem. 2002 Oct 25;277(43):40919-29
references: 12167638
references: Mol Vis. 2004 Apr 16;10:281-8
references: 15105792
references: Exp Eye Res. 2006 Jan;82(1):33-45
references: 16005870
references: Stem Cells. 2007 Jun;25(6):1529-38
references: 17363553
references: Arthritis Rheum. 2000 Dec;43(12):2807-17
references: 11145040
references: Acta Ophthalmol (Copenh). 1971;49(5):779-89
references: 5171922
references: J Biomed Opt. 2005 Mar-Apr;10(2):024017
references: 15910091
references: J Clin Invest. 1983 Jul;72(1):52-62
references: 6603476
references: Ultrastruct Pathol. 1997 Nov-Dec;21(6):537-44
references: 9355236
references: J Immunol. 2000 Jul 15;165(2):779-85
references: 10878351
references: Anat Histol Embryol. 2003 Oct;32(5):257-62
references: 12969024
references: Arch Oral Biol. 1999 May;44 Suppl 1:S21-5
references: 10414851
references: J Oral Med. 1975 Jan-Mar;30(1):24-8
references: 45939
references: Arthritis Rheum. 2003 Sep;48(9):2573-84
references: 13130477
references: Differentiation. 2003 Jun;71(4-5):291-8
references: 12823230
references: Clin Exp Immunol. 1999 Oct;118(1):154-63
references: 10540173
references: J Rheumatol. 1998 Dec;25(12):2371-80
references: 9858432
references: Rheumatology (Oxford). 2004 Dec;43(12):1476-9
references: 15316122
references: Int Immunol. 2000 Mar;12(3):313-24
references: 10700466
references: Arch Histol Cytol. 2003 Dec;66(5):407-18
references: 15018143
references: Arch Oral Biol. 1996 Oct;41(10):951-8
references: 9031702
references: Scand J Immunol. 2003 Nov;58(5):550-65
references: 14629627
references: Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4293-301
references: 15557435
references: J Clin Invest. 1996 Apr 15;97(8):1969-77
references: 8621782
references: Exp Eye Res. 2004 Nov;79(5):665-75
references: 15500825
references: J Clin Invest. 2000 Jan;105(1):21-34
references: 10619858
references: Aust Dent J. 1982 Oct;27(5):288-90
references: 6962691
references: J Morphol. 1989 Jul;201(1):39-57
references: 2664187
references: Invest Ophthalmol Vis Sci. 1989 Sep;30(9):2002-11
references: 2777519
references: Exp Eye Res. 2000 Jul;71(1):11-22
references: 10880272
references: Adv Drug Deliv Rev. 2006 Sep 15;58(7):878-96
references: 17011064
references: J Rheumatol. 1996 Feb;23(2):313-20
references: 8882038
references: Ann Rheum Dis. 2006 Feb;65(2):178-83
references: 16014676
references: Arch Histol Cytol. 1996 Dec;59(5):505-13
references: 9037387
references: Anat Embryol (Berl). 1998 Jul;198(1):1-12
references: 9683063
references: J Cell Biochem. 2001 Mar 26;81(2):220-8
references: 11241662
references: Arch Oral Biol. 1997 Jun;42(6):443-54
references: 9382709
references: Matrix Biol. 1998 Oct;17(5):335-47
references: 9822200
references: Arthritis Rheum. 1986 May;29(5):577-85
references: 3718551
references: Mayo Clin Proc. 2001 Jun;76(6):593-9
references: 11393497
references: Clin Immunol. 2002 Nov;105(2):223-32
references: 12482397
references: J Histochem Cytochem. 2005 Apr;53(4):431-43
references: 15805418
references: Proc Natl Acad Sci U S A. 1997 May 27;94(11):5767-71
references: 9159148
references: Nat Rev Immunol. 2002 May;2(5):309-22
references: 12033737
references: Anat Rec. 1992 Nov;234(3):335-47
references: 1443662
references: J Leukoc Biol. 2000 Feb;67(2):149-59
references: 10670574
references: J Immunol. 1996 Jan 1;156(1):1-4
references: 8598448
references: Connect Tissue Res. 1995;31(2):133-40
references: 15612329
references: Arch Pathol. 1972 Aug;94(2):187-91
references: 4114784
references: J Clin Immunol. 2006 Jul;26(4):299-307
references: 16652230
references: Arch Med Res. 2006 Nov;37(8):921-32
references: 17045106
references: Lancet. 2001 Mar 3;357(9257):688-9
references: 11247557
references: Scand J Immunol. 2005 Jan;61(1):36-50
references: 15644121