title: Identification of two new arthritis severity loci that regulate levels of autoantibodies, interleukin-1β, and joint damage in pristane- and collagen-induced arthritis.
abstract: OBJECTIVE
  Cia3 is a locus on rat chromosome 4 that regulates severity and joint damage in collagen- and pristane-induced arthritis (CIA and PIA). This study was undertaken to refine the Cia3 gene-containing interval toward gene identification and obtain insights into its mode of action.
  
  
  METHODS
  Five DA.F344(Cia3) subcongenic rat strains were generated and studied using the PIA and CIA models. Levels of antibodies against type II collagen (both allo- and autoantibodies) were measured. Joints and synovial tissue were collected 32 days after the induction of PIA (chronic stage) for histologic and quantitative polymerase chain reaction analysis of interleukin-1β (IL-1β) and matrix metalloproteinase (MMP) levels.
  
  
  RESULTS
  Three subcongenic strains sharing the centromeric Cia3d interval were protected and 2 subcongenic strains sharing the telomeric Cia3g interval, which did not overlap with Cia3d, were also protected, developing significantly less severe CIA and PIA. Normal joint architecture was preserved in DA.F344(Cia3) and DA.F344(Cia3d) congenic rats with PIA, while DA rats had pronounced synovial hyperplasia, angiogenesis, inflammatory infiltration, and bone or cartilage erosions. The DA.F344(Cia3d) and DA.F344(Cia3g) strains had significantly lower synovial levels of IL-1β (5-fold and nearly 2-fold, respectively [the latter not reaching statistical significance]), MMP-1 (expressed predominantly in DA rats), MMP-3 (79-fold and 8-fold, respectively), and MMP-14 (21-fold and 1.4-fold, respectively) and reduced levels of pathogenic autoantibodies against type II collagen, compared with DA rats.
  
  
  CONCLUSIONS
  We have identified 2 new arthritis severity and articular damage loci within Cia3. These loci regulate pathogenic processes in 2 different models of rheumatoid arthritis, and the identification of these genes has the potential to generate new targets for therapies aimed at reducing disease severity and articular damage, and may additionally have prognostic value.
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Brenner
authors.forename: Teresina
authors.initials: T
authors.lastname: Laragione
authors.forename: Anish
authors.initials: A
authors.lastname: Shah
authors.forename: Adriana
authors.initials: A
authors.lastname: Mello
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Wilder
authors.forename: Pércio S
authors.initials: PS
authors.lastname: Gulko
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000276:immunology / Q000633:toxicity*; D024043:Collagen Type II / Q000276:immunology; D018450:Disease Progression; D015870:Gene Expression; D005819:Genetic Markers; D007166:Immunosuppressive Agents / Q000633:toxicity*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D012720:Severity of Illness Index; D013045:Species Specificity; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013729:Terpenes / Q000276:immunology / Q000633:toxicity*
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D024043:Collagen Type II; D005819:Genetic Markers; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D013729:Terpenes; C009042:pristane; D003094:Collagen; D045726:Metalloproteases
references.citation: J Exp Med. 1991 May 1;173(5):1121-32
references.pmid: 2022923
references.citation: Clin Exp Immunol. 2004 Jul;137(1):65-73
references.pmid: 15196245
references.citation: Ann Rheum Dis. 2003 May;62(5):427-30
references.pmid: 12695154
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13859-64
references.pmid: 9811891
references.citation: Arthritis Rheum. 1996 Oct;39(10):1720-7
references.pmid: 8843863
references.citation: J Clin Invest. 1999 Jan;103(1):47-54
references.pmid: 9884333
references.citation: J Clin Invest. 1995 Feb;95(2):456-63
references.pmid: 7532184
references.citation: Clin Exp Immunol. 1998 Mar;111(3):521-6
references.pmid: 9528892
references.citation: Ann Rheum Dis. 2004 Jun;63(6):675-80
references.pmid: 15140774
references.citation: Am J Pathol. 2000 Oct;157(4):1187-96
references.pmid: 11021823
references.citation: Arthritis Rheum. 2002 Apr;46(4):1075-85
references.pmid: 11953987
references.citation: Arthritis Rheum. 1994 Apr;37(4):481-94
references.pmid: 8147925
references.citation: Genes Immun. 2006 Jun;7(4):277-86
references.pmid: 16691188
references.citation: Arthritis Res Ther. 2008;10(4):R92
references.pmid: 18706093
references.citation: J Immunol. 1997 Oct 1;159(7):3604-12
references.pmid: 9317160
references.citation: Arthritis Rheum. 2000 Aug;43(8):1719-28
references.pmid: 10943861
references.citation: J Immunol. 2000 Jun 15;164(12):6495-502
references.pmid: 10843707
references.citation: Am J Pathol. 1996 Nov;149(5):1675-83
references.pmid: 8909256
references.citation: Ann Rheum Dis. 2010 Mar;69(3):476-82
references.pmid: 20124360
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):402-6
references.pmid: 8552648
references.citation: Arthritis Rheum. 2002 Aug;46(8):2225-34
references.pmid: 12209529
references.citation: J Immunol. 1995 Feb 1;154(3):1432-9
references.pmid: 7822808
references.citation: N Engl J Med. 2007 Sep 20;357(12):1199-209
references.pmid: 17804836
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9979-84
references.pmid: 9707586
references.citation: Arthritis Rheum. 2000 Jun;43(6):1278-89
references.pmid: 10857786
references.citation: J Autoimmun. 1991 Dec;4(6):871-80
references.pmid: 1812893
references.citation: Biochem Biophys Res Commun. 2001 Feb 23;281(2):562-8
references.pmid: 11181084
references.citation: Arthritis Rheum. 2004 Aug;50(8):2695-705
references.pmid: 15334486
references.citation: J Investig Med. 1998 Feb;46(2):27-41
references.pmid: 9549225
references.citation: Am J Pathol. 1995 Jan;146(1):239-49
references.pmid: 7856731
references.citation: Arthritis Rheum. 2005 Jan;52(1):322-32
references.pmid: 15641042
references.citation: Curr Dir Autoimmun. 1999;1:121-65
references.pmid: 11791440
references.citation: Nat Genet. 1998 Dec;20(4):401-4
references.pmid: 9843218
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6383-7
references.pmid: 9600974
references.citation: Hum Mol Genet. 2000 Sep 22;9(15):2241-50
references.pmid: 11001927
references.citation: J Rheumatol Suppl. 1996 Mar;44:31-3
references.pmid: 8833048
references.citation: Am J Hum Genet. 2004 Aug;75(2):330-7
references.pmid: 15208781
references.citation: Genes Immun. 2010 Apr;11(3):239-45
references.pmid: 20200546
references.citation: N Engl J Med. 2004 Jun 17;350(25):2572-81
references.pmid: 15201414
references.citation: Blood. 2011 Apr 7;117(14):3720-32
references.pmid: 21304099
references.citation: Arthritis Rheum. 2007 Aug;56(8):2620-32
references.pmid: 17665455
references.citation: J Immunol. 2005 Jun 15;174(12):7894-903
references.pmid: 15944295
references.citation: Arthritis Rheum. 1998 Dec;41(12):2122-31
references.pmid: 9870869
references.citation: Nat Genet. 1996 Sep;14(1):82-5
references.pmid: 8782824
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Immunol. 1999 Nov 1;163(9):5049-55
references.pmid: 10528210
references.citation: Arthritis Rheum. 2000 May;43(5):1001-9
references.pmid: 10817552