Copper chelation with tetrathiomolybdate suppresses adjuvant-induced arthritis and inflammation-associated cachexia in rats

Atsushi Omoto,Igor Prudovsky,Makie Yoshida,Toshikazu Yoshikawa,Makoto Wada,Yasunori Tubouchi,Masataka Kohno,Hidetaka Ishino,Mizuho Kimura,Yutaka Kawahito,Hajime Sano,Rikio Yoshimura

doi:10.1186/ar1801

Abstract

Tetrathiomolybdate (TM), a drug developed for Wilson's disease, produces an anti-angiogenic and anti-inflammatory effect by reducing systemic copper levels. TM therapy has proved effective in inhibiting the growth of tumors in animal tumor models and in cancer patients. We have hypothesized that TM may be used for the therapy of rheumatoid arthritis and have examined the efficacy of TM on adjuvant-induced arthritis in the rat, which is a model of acute inflammatory arthritis and inflammatory cachexia. TM delayed the onset of and suppressed the severity of clinical arthritis on both paw volume and the arthritis score. Histological examination demonstrated that TM significantly reduces the synovial hyperplasia and inflammatory cell invasion in joint tissues. Interestingly, TM can inhibit the expression of vascular endothelial growth factor in serum synovial tissues, especially in endothelial cells and macrophages. Moreover, the extent of pannus formation, which leads to bone destruction, is correlated with the content of vascular endothelial growth factor in the serum. There was no mortality in TM-treated rat abnormalities. TM also suppressed inflammatory cachexia. We suggest that copper deficiency induced by TM is a potent approach both to inhibit the progression of rheumatoid arthritis with minimal adverse effects and to improve the well-being of rheumatoid arthritis patients.

Highlights

Rheumatoid arthritis (RA) is a chronic, destructive inflammatory polyarticular joint disease
We examined whether TM has the potency to suppress chronic inflammation, pannus formation, and angiogenesis in the course of adjuvant-induced arthritis (AIA) in female Lewis rats
We examined whether copper chelation with TM reduces the production of Vascular endothelial growth factor (VEGF) in serum and synovium of AIA rats and suppresses inflammatory cachexia in AIA rats

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, destructive inflammatory polyarticular joint disease. It is characterized by massive synovial proliferation and subintimal infiltration of inflammatory cells, which along with angiogenesis leads to the formation of a very aggressive tissue called pannus [1,2]. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of RA [3,5,6]. Immunohistochemical and in situ hybridization studies indicate that VEGF is strongly expressed in subsynovial macrophages, in fibroblasts surrounding microvessels, in vascular smooth muscle cells, and in synoviocytes [7,8,9]. The VEGF level in synovial fluid and tissues correlates with the clinical severity of RA and with the degree of joint

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