Article Text


Administration of IL-18BP by gene therapy reduces inflammation and prevents joint destruction by downregulation of MMP9 in rat AIA: role of MMP9 in bone and joint destruction in arthritis
  1. Hubert Marotte1,2,
  2. Salahuddin Ahmed1,
  3. M Asif Amin1,
  4. Jeffrey H Ruth1,
  5. Phillip L Campbell1,
  6. Bradley J Rabquer1,
  7. Charles Lesch1,
  8. Benjamin P Lewis1,
  9. Jean Dudler3,
  10. Alisa E Koch1,4
  1. 1Department of Internal Medicine/Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
  2. 2INSERM U890, Rheumatology Department, University Hospital of St-Etienne, St-Etienne, France
  3. 3Service de Rhumatologie, Médecine Physique et Rééducation, CHUV, Lausanne, Switzerland
  4. 4Department of Veterans Affairs, VA Medical Service, Ann Arbor, Michigan, USA


Background and objectives Interleukin 18 (IL-18) is a pleiotropic cytokine involved in rheumatoid arthritis (RA) pathogenesis. This study was carried out to evaluate the efficacy of IL-18 binding protein (IL-18BP) gene therapy in the rat adjuvant-induced arthritis (AIA) model and to decipher the mechanisms by which IL-18BP delivery lessens bone destruction.

Materials and methods Arthritis was induced in female Lewis rat by Mycobacterium butyricum and the mRNA expression of IL-18 and IL-18BP was determined in the joints. In a preventive study, rats were divided into an adenovirus producing IL-18BP-Fc (AdmIL-18BP-Fc) group (n=8) and an adenovirus producing green fluorescent protein (AdGFP) group (n=7). On day 8 after AIA induction, adenoviruses were injected. Clinical parameters were assessed. At day 18, during maximal arthritis, the rats were euthanized, ankles were collected and x-rays were performed. mRNA and protein were extracted from joints for analysis by quantitative reverse transcriptase-PCR, multiplex, Western blot and zymography.

Results The authors observed a decrease in the (IL-18BP/IL-18) ratio from day 7 to 45. Administration of AdmIL-18BPd-Fc decreased clinical parameters and prevented bone and joint destruction compared to AdGFP administration. IL-18BP delivery reduced the (receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG)) ratio by 70%, the matrix metalloproteinase 9 (MMP9) level by 33% and the tartrate-resistant acid phosphatase (TRAP) level by 44% in the joint homogenates from AdmIL-18BPd-Fc compared to AdGFP treated rats.

Conclusions In rat AIA, a decrease in the (IL-18BP/IL-18) ratio was observed. IL-18BP delivery prevented joint and bone destruction by downregulating MMP9, (RANKL/OPG) and TRAP, suggesting a potential benefit of a similar therapy in RA.

Abstract topics Towards novel therapeutic strategies.

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