Article Text

PDF

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

Abstract

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.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.