Suppression of experimental osteoarthritis by adenovirus-mediated double gene transfer  

作　　者：WANG Hai-jun YU Chang-long Kishi Hiroyuki Motoki Kazumi MAO Ze-bin Muraguchi Atsushi 

机构地区：[1]Institute of Sports Medicine, Peking University Third Hospital,Beijing 100083, China [2]Department of Immunology, Faculty of Medicine, University ofToyama, Toyama 930-0194, Japan [3]Department of Biochemistry and Molecular Biology, PekingUniversity School of Basic Medical Sciences, Beijing 100083,China

出　　处：《Chinese Medical Journal》2006年第16期1365-1373,共9页中华医学杂志（英文版）

摘　　要：Background Osteoarthritis （OA） is a chronic and incurable disease, lacking effective treatment. Gene therapy offers a radical different approach to the treatment of arthritis. Even though the etiology of OA remains unclear, there is now considerable evidence to suggest that interleukin-1 （IL-1） and tumor necrosis factor- α （TNF- α ） are the main mediators in the pathogenesis of OA. The goal of this study was to determine the efficacy of local expression of interleukin-1 receptor antagonist （IL-1Ra） and soluble tumor necrosis factor- α receptor type Ⅰ （sTNF-RI） by direct adenoviral-mediated intra-articular gene delivery in the rabbit model of osteoarthritis. Methods Adenoviral vectors containing IL-1Ra or sTNF-RI genes were constructed. OA was induced in both hind knees of 12 New Zealand white rabbits by the excision of the medial collateral ligament plus medial meniscectomy. Five days after surgery, approximately 1 × 10^8 plaque-forming units （pfu） of adenovirus were injected into the joint space of the knee through the patellar tendon. A total of 12 operated rabbits were divided into four groups. Three experimental rabbit groups received 1 × 10^8 pfu of adenovirus encoding either IL-1Ra （3 rabbits）, sTNF-RI （3 rabbits） or IL-1Ra and sTNF-RI in combination （3 rabbits）, into both knee joints respectively. An inflamed control group of 3 rabbits received approximately 1 × 10^8 pfu of Ad-GFP into both joints. Three days after injection of the adenovirus, both knees of each rabbit were lavaged with 1 ml of saline solution through the patellar tendon. At day 7, the rabbits were sacrificed, and the knees were lavaged, dissected and analyzed for effects of transgene expression. Levels of IL-1Ra and sTNF-RI expression in recovered lavage fluids were measured using a cytokine ELISA kit. Cartilage from the lesion areas of medial femoral condyle and synovium were fixed, embedded, sectioned and stained with hematoxylin and eosin （cartilage and synovium） and toluidine blue （carBackground Osteoarthritis （OA） is a chronic and incurable disease, lacking effective treatment. Gene therapy offers a radical different approach to the treatment of arthritis. Even though the etiology of OA remains unclear, there is now considerable evidence to suggest that interleukin-1 （IL-1） and tumor necrosis factor- α （TNF- α ） are the main mediators in the pathogenesis of OA. The goal of this study was to determine the efficacy of local expression of interleukin-1 receptor antagonist （IL-1Ra） and soluble tumor necrosis factor- α receptor type Ⅰ （sTNF-RI） by direct adenoviral-mediated intra-articular gene delivery in the rabbit model of osteoarthritis. Methods Adenoviral vectors containing IL-1Ra or sTNF-RI genes were constructed. OA was induced in both hind knees of 12 New Zealand white rabbits by the excision of the medial collateral ligament plus medial meniscectomy. Five days after surgery, approximately 1 × 10^8 plaque-forming units （pfu） of adenovirus were injected into the joint space of the knee through the patellar tendon. A total of 12 operated rabbits were divided into four groups. Three experimental rabbit groups received 1 × 10^8 pfu of adenovirus encoding either IL-1Ra （3 rabbits）, sTNF-RI （3 rabbits） or IL-1Ra and sTNF-RI in combination （3 rabbits）, into both knee joints respectively. An inflamed control group of 3 rabbits received approximately 1 × 10^8 pfu of Ad-GFP into both joints. Three days after injection of the adenovirus, both knees of each rabbit were lavaged with 1 ml of saline solution through the patellar tendon. At day 7, the rabbits were sacrificed, and the knees were lavaged, dissected and analyzed for effects of transgene expression. Levels of IL-1Ra and sTNF-RI expression in recovered lavage fluids were measured using a cytokine ELISA kit. Cartilage from the lesion areas of medial femoral condyle and synovium were fixed, embedded, sectioned and stained with hematoxylin and eosin （cartilage and synovium） and toluidine blue （car

关 键 词：OSTEOARTHRITIS receptors  interleukin- 1 tumor necrosis factor-alpha gene therapy 

分 类 号：R684.3[医药卫生—骨科学]