title: Epirubicin potentiates recombinant adeno-associated virus type 2/5-mediated TRAIL expression in fibroblast-like synoviocytes and augments the antiarthritic effects of rAAV2/5-TRAIL.
abstract: OBJECTIVE
  Synovial cells in rheumatoid synovium display abnormal proliferation, which leads to joint destruction. TRAIL has been described as a proapoptotic factor in fibroblast-like synoviocytes (FLS). This study was undertaken to investigate the functions of rAAV2/5-TRAIL in human FLS and in arthritic mice.
  
  
  METHODS
  Primary human FLS were infected with rAAV2/5-TRAIL in the presence or absence of epirubicin. Transgene expression was monitored by both enzyme-linked immunosorbent assay and flow cytometry. The disease-modulating activity of epirubicin plus rAAV2/5-TRAIL was investigated in mice with collagen-induced arthritis (CIA).
  
  
  RESULTS
  Subtoxic doses of epirubicin potentiated rAAV2/5-mediated TRAIL expression in FLS and simultaneously enhanced the sensitivity of FLS to TRAIL. Epirubicin treatment up-regulated death receptor 4 (DR-4) and DR-5 expression and down-regulated FLIP expression, thereby enhancing the activation of procaspase 3, procaspase 8, and procaspase 9. An in vivo study showed that the combination of rAAV2/5-TRAIL gene therapy and epirubicin chemotherapy provided augmented antiarthritic effects in a mouse model of CIA. The intraarticular injection of rAAV2/5-TRAIL combined with epirubicin treatment significantly reduced the severity and incidence of CIA and joint swelling in the animals. Histologic evaluations revealed that inflammatory cell infiltration, cartilage destruction, and bone erosion were significantly reduced in the joints of the mice receiving the synthetic treatment. Results of a viral genome copy number assay indicated that epirubicin dramatically augmented the expression of rAAV2/5-TRAIL without altering its tissue distribution.
  
  
  CONCLUSIONS
  These results suggest that epirubicin enhances the antiarthritic effect of rAAV2/5-TRAIL and that combination treatment might be an important therapeutic alternative, with practical significance for rheumatoid arthritis.
authors: Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Juan
authors: J
authors: Shi
authors: Zhijuan
authors: Z
authors: Diao
authors: Jiansuo
authors: J
authors: Zhou
authors: Jieqing
authors: J
authors: Zhu
authors: Haiqin
authors: H
authors: Yuan
authors: Xin
authors: X
authors: You
authors: Yanxin
authors: Y
authors: Liu
authors: Dexian
authors: D
authors: Zheng
mesh_terms: D000256:Adenoviridae / Q000145:classification / Q000235:genetics* / Q000276:immunology; D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000096:biosynthesis; D001169:Arthritis, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D015251:Epirubicin / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D011994:Recombinant Proteins; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000914:Antibodies, Viral; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D015251:Epirubicin