Copper chelation with tetrathiomolybdate suppresses adjuvant-induced arthritis and inflammation-associated cachexia in rats.
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.
Omoto
Atsushi
A
Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. omochan@koto.kpu-m.ac.jp
Kawahito
Yutaka
Y
Prudovsky
Igor
I
Tubouchi
Yasunori
Y
Kimura
Mizuho
M
Ishino
Hidetaka
H
Wada
Makoto
M
Yoshida
Makie
M
Kohno
Masataka
M
Yoshimura
Rikio
R
Yoshikawa
Toshikazu
T
Sano
Hajime
H
D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002100:Cachexia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002614:Chelating Agents / Q000627:therapeutic use*; D015913:Chelation Therapy; D003300:Copper / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006614:Hindlimb / Q000473:pathology; D007124:Immunoenzyme Techniques; D007596:Joints / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008982:Molybdenum / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D015415:Biomarkers; D002614:Chelating Agents; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate