Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice.
BACKGROUND
Dichloroacetate (DCA) has been in clinical use for the treatment of lactacidosis and inherited mitochondrial disorders. It has potent anti-tumor effects both in vivo and in vitro, facilitating apoptosis and inhibiting proliferation. The pro-apoptotic and anti-proliferative properties of DCA prompted us to investigate the effects of this compound in arthritis.


METHODS
In the present study, we used DCA to treat murine collagen type II (CII)-induced arthritis (CIA), an experimental model of rheumatoid arthritis. DBA/1 mice were treated with DCA given in drinking water.


RESULTS
Mice treated with DCA displayed much slower onset of CIA and significantly lower severity (P < 0.0001) and much lower frequency (36% in DCA group vs. 86% in control group) of arthritis. Also, cartilage and joint destruction was significantly decreased following DCA treatment (P = 0.005). Moreover, DCA prevented arthritis-induced cortical bone mineral loss. This clinical picture was also reflected by lower levels of anti-CII antibodies in DCA-treated versus control mice, indicating that DCA affected the humoral response. In contrast, DCA had no effect on T cell- or granulocyte-mediated responses. The beneficial effect of DCA was present in female DBA/1 mice only. This was due in part to the effect of estrogen, since ovariectomized mice did not benefit from DCA treatment to the same extent as sham-operated controls (day 30, 38.7% of ovarectomized mice had arthritis vs. only 3.4% in sham-operated group).


CONCLUSIONS
Our results indicate that DCA delays the onset and alleviates the progression of CIA in an estrogen-dependent manner.
Bian
Li
L
Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10A, Box 480, SE-405 30, Gothenburg, Sweden. li.bian@rheuma.gu.se
Josefsson
Elisabet
E
Jonsson
Ing-Marie
IM
Verdrengh
Margareta
M
Ohlsson
Claes
C
Bokarewa
Maria
M
Tarkowski
Andrej
A
Magnusson
Mattias
M
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000097:blood / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D003094:Collagen / Q000276:immunology; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D010052:Ovariectomy; D013601:T-Lymphocytes / Q000187:drug effects
D001323:Autoantibodies; D004967:Estrogens; D003094:Collagen; D003999:Dichloroacetic Acid