title: Disease-regulated local IL-10 gene therapy diminishes synovitis and cartilage proteoglycan depletion in experimental arthritis.
abstract: OBJECTIVE
  Rheumatoid arthritis is a chronic destructive autoimmune disease, but the course is unpredictable in individual patients. An attractive treatment would provide a disease-regulated therapy that offers personalised drug delivery. Therefore, we expressed the anti-inflammatory interleukin-10 (IL-10) gene under the control of inflammation-dependent promoters in a mouse model of arthritis.
  
  
  METHODS
  Proximal promoters of S100a8, Cxcl1, Mmp13, Saa3, IL-1b and Tsg6 were selected by whole-genome expression analysis of inflamed synovial tissues from arthritic mice. Mice were injected intraarticularly in knee joints with lentiviral vectors expressing a luciferase reporter or the therapeutic protein IL-10 under control of the Saa3 or Mmp13 promoter. After 4 days, arthritis was induced by intraarticular injection of streptococcal cell walls (SCW). At different time points after arthritis induction, in vivo bioluminescent imaging was performed and knee joints were dissected for histological and RNA analysis.
  
  
  RESULTS
  The disease-regulated promoter-luciferase reporter constructs showed different activation profiles during the course of the disease. The Saa3 and Mmp13 promoters were significantly induced at day 1 or day 4 after arthritis induction respectively and selected for further research. Overexpression of IL-10 using these two disease-inducible promoters resulted in less synovitis and markedly diminished cartilage proteoglycan depletion and in upregulation of IL-1Ra and SOCS3 gene expression.
  
  
  CONCLUSIONS
  Our study shows that promoters of genes that are expressed locally during arthritis can be candidates for disease-regulated overexpression of biologics into arthritic joints, as shown for IL-10 in SCW arthritis. The disease-inducible approach might be promising for future tailor-made local gene therapy in arthritis.
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Eline A
authors.initials: EA
authors.lastname: Vermeij
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mathijs G A
authors.initials: MG
authors.lastname: Broeren
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Miranda B
authors.initials: MB
authors.lastname: Bennink
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Onno J
authors.initials: OJ
authors.lastname: Arntz
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Gjertsson
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001172:Arthritis, Rheumatoid; D002358:Cartilage, Articular / Q000378:metabolism*; D002473:Cell Wall / Q000276:immunology; D015870:Gene Expression; D015316:Genetic Therapy; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D016753:Interleukin-10; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011509:Proteoglycans / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000235:genetics; D013291:Streptococcus / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D013585:Synovitis / Q000276:immunology / Q000473:pathology / Q000628:therapy*
chemical_list: C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D011509:Proteoglycans; D012333:RNA, Messenger; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
keywords: Arthritis; Cytokines; Inflammation; Synovitis; Treatment