Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees.
To examine the effect of transforming growth factor (TGF)-beta1 on the regulation of cartilage synthesis and other articular pathologies, we used adenovirus-mediated intra-articular gene transfer of TGF-beta1 to both naïve and arthritic rabbit knee joints. Increasing doses of adenoviral vector expressing TGF-beta1 were injected into normal and antigen-induced arthritis rabbit knee joints through the patellar tendon, with the same doses of an adenoviral vector expressing luciferase injected into the contralateral knees as the control. Intra-articular injection of adenoviral vector expressing TGF-beta1 into the rabbit knee resulted in dose-dependent TGF-beta1 expression in the synovial fluid. Intra-articular TGF-beta1 expression in both naïve and arthritic rabbit knee joints resulted in significant pathological changes in the rabbit knee as well as in adjacent muscle tissue. The observed changes induced by elevated TGF-beta1 included inhibition of white blood cell infiltration, stimulation of glycosaminoglycan release and nitric oxide production, and induction of fibrogenesis and muscle edema. In addition, induction of chondrogenesis within the synovial lining was observed. These results suggest that even though TGF-beta1 may have anti-inflammatory properties, it is unable to stimulate repair of damaged cartilage, even stimulating cartilage degradation. Gene transfer of TGF-beta1 to the synovium is thus not suitable for treating intra-articular pathologies.
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Zhibao
Z
Mi
Steven C
SC
Ghivizzani
Eric
E
Lechman
Joseph C
JC
Glorioso
Christopher H
CH
Evans
Paul D
PD
Robbins
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004487:Edema / Q000209:etiology; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000096:biosynthesis / Q000627:therapeutic use; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011817:Rabbits; D016212:Transforming Growth Factor beta / Q000009:adverse effects* / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1
D000276:Adjuvants, Immunologic; D006025:Glycosaminoglycans; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide