Copper Chelation With Tetrathiomolybdate Suppresses Adjuvant-Induced Arthritis and Inflammation-Associated Cachexia in Rats

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

Disclosures

Arthritis Res Ther. 2005;7(6):R1174-R1182. 

In This Article

Abstract and Introduction

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.

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] Expansion of the pannus induces bone erosion and cartilage thinning, leading to the loss of joint function. The rheumatoid pannus can thus be considered a local tumor. One of the earliest phenomena observed in RA is synovial neovascular formation delivering nutrients and oxygen to this proliferating pannus.[3] It has been demonstrated that angiogenesis inhibitors can inhibit the growth of pannus in animal arthritis models.[4] 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] VEGF expression is activated at the very early stages of RA, and it continues throughout the course of the disease.[10,11] The VEGF level in synovial fluid and tissues correlates with the clinical severity of RA and with the degree of joint destruction.[10] Moreover, VEGF mediates the recruitment, chemotaxis, and proliferation of osteoclast precursor macrophages, leading to bone destruction.[11,12]

RA is also characterized by increased production of the inflammatory cytokines tumor necrosis factor alpha (TNF-α),[1] IL-1α,[13] IL-1β,[1] and fibroblast growth factor (FGF) 1.[14] TNF-α appears to be a key mediator in the disease process, and IL-1β plays a permissive role by acting to shift the whole-body protein metabolism towards net catabolism, to elevate resting energy expenditure, and to increase joint pain and stiffness.[15] Treatment with antibodies against TNF-α, IL-1α, and IL-1β attenuated RA in the experimental mouse model.[16] FGF-1 is important for the growth of synoviocytes in the course of RA.[17]

Rheumatoid cachexia was first described more than a century ago.[18] However, it has not been recognized as a common problem among patients with RA until relatively recently. Rheumatoid cachexia leads to muscle weakness, osteoporosis, and a loss of functional capacity. It also increases susceptibility to infection,[19] and is believed to accelerate morbidity and mortality in RA.[15]

Copper is an essential trace element that acts as a cofactor for a variety of enzymes by virtue of its ability to accept and donate electrons under physiologic conditions.[20] Additionally, copper ions have recently been demonstrated to be required for the assembly of multiprotein release complexes in the process of stress-induced nonclassical release of FGF-1 and IL-1α.[21,22,23] These two proteins lack signal sequences in their primary structures, and cannot be released through the classical endoplasmic reticulum-Golgi pathway. Their nonclassical export involves copper-dependent association with a small calcium-binding protein, S100A13.

Tetrathiomolybdate (TM), which forms a stable tripartite complex with copper and protein, is a copper-lowering agent that has been evaluated extensively in the treatment of Wilson's disease.[24] TM treatment decreases serum copper levels and attenuates angiogenesis and tumor growth in animal tumor models.[25,26,27] The hypothesis underlying this approach is that one or more copper-containing or copper-binding angiogenic proteins (e.g. VEGF, FGF-1, FGF-2, angiogenin, angiotropin, or others) require higher levels of copper to be active than are required for basic cellular needs.[28] In fact, the antitumor activity of TM was evaluated in patients with advanced kidney cancer in a phase II trial.[29]

Alternatively, the in vivo effects of TM may be explained by its ability to block the release of FGF-1 and IL-1α, both known as potent proangiogenic and proinflammatory polypeptides. Indeed, the inhibition of restenosis by TM in the model of damaged rat carotid artery was accompanied by the downregulation of FGF-1 and IL-1α levels in the vessel wall.[22] Additionally, copper is known to play an important role in the development and maintenance of the immune system.[30] Some reports revealed that the possibility of inhibiting both fibrotic response and inflammatory response by copper chelation is due to the suppression of transforming growth factor beta and TNF-α production.[31,32]

The serum copper level in RA patients has been reported to be high,[33] and the IL-1β and TNF-α serum content might correlate with the serum copper level in RA patients.[34] In addition, D-penicillamine (another anticopper agent) has been used as the therapy for RA for many years. A previous study suggested that D-penicillamine might regress rheumatoid synovial hyperplasia via Fas-mediated apoptosis, but the mechanism of the effect of D-penicillamine is still unknown.[35] In animal studies, TM is a more fast-acting, more potent, copper chelating agent than D-penicillamine.[36] We hypothesized that the anticopper drug TM can be useful for the treatment of RA through inhibition of proangiogenic and proinflammatory cytokines. 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 also examined whether copper chelation with TM reduces the production of VEGF in serum and synovium of AIA rats and suppresses inflammatory cachexia in AIA rats.

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