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Open Access Research article

Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees

Zhibao Mi1, Steven C Ghivizzani13, Eric Lechman1, Joseph C Glorioso1, Christopher H Evans23 and Paul D Robbins1*

Author Affiliations

1 Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

2 Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

3 Present address: Center for Molecular Orthopaedics, Harvard Medical School, Boston, Massacuhsetts, USA

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Arthritis Res Ther 2003, 5:R132-R139  doi:10.1186/ar745

Published: 12 March 2003

Abstract

To examine the effect of transforming growth factor (TGF)-β1 on the regulation of cartilage synthesis and other articular pathologies, we used adenovirus-mediated intra-articular gene transfer of TGF-β1 to both naïve and arthritic rabbit knee joints. Increasing doses of adenoviral vector expressing TGF-β1 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-β1 into the rabbit knee resulted in dose-dependent TGF-β1 expression in the synovial fluid. Intra-articular TGF-β1 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-β1 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-β1 may have anti-inflammatory properties, it is unable to stimulate repair of damaged cartilage, even stimulating cartilage degradation. Gene transfer of TGF-β1 to the synovium is thus not suitable for treating intra-articular pathologies.

Keywords:
arthritis gene therapy; cartilage degradation; inflammatory; nitric oxide; rabbit model; transforming growth factor-β1