Inhibition of disease progression by a novel retinoid antagonist in animal models of arthritis.
OBJECTIVE
To investigate the usefulness of a novel retinoic acid receptor (RAR) antagonist (BMS-189453) in animal models of arthritis.


METHODS
BMS-189453 was tested in HIG-82 rabbit synovial fibroblasts to determine its ability to repress collagenase (matrix metalloproteinase-1, MMP-1) mRNA expression in vitro. Cells were stimulated with phorbol myristate acetate or interleukin 1 beta and mRNA quantified by slot-blot analysis. In vivo, BMS-189453 was evaluated in 2 animal models of arthritis: collagen induced arthritis (CIA) in mice and streptococcal cell wall induced arthritis (SCWA) in rats. Clinical scores for arthritis were recorded weekly. At the end of each study, limbs were evaluated histologically. In CIA, these results were correlated with mRNA levels for collagenase-3 (MMP-13) and stromelysin-1 (MMP-3) as determined by Northern blot.


RESULTS
BMS-189453 reduced MMP-1 expression in HIG-82 synovial fibroblasts in culture. BMS-189453 treatment blocked the clinical progression of arthritis beyond soft tissue inflammation in the CIA model. In the SCWA model, BMS-189453 treatment resulted in significantly reduced swelling with no notable progression to joint distortion/destruction. Histological evaluation of the joints from animals in both models confirmed this result. Analysis of mRNA from the CIA paws showed that BMS-189453 prevented the overexpression of MMP-13 and MMP-3 in arthritic joints.


CONCLUSIONS
Improvement in clinical and histologic variables in 2 separate animal models, along with simultaneous reduction in MMP expression in the affected joint, suggests that RAR antagonists such as BMS-189453 may be useful as agents to treat rheumatoid arthritis and for determining the role of MMP in disease progression. This is the first study to show the clinical potential of RAR antagonists in arthritis.
Beehler
Blake C
BC
Department of Biochemical Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Buffalo, New York, USA. blake.beehler@bms.com
Hei
Yong-Jiang
YJ
Chen
Simon
S
Lupisella
John A
JA
Ostrowski
Jacek
J
Starrett
John E
JE
Tortolani
David
D
Tramposch
Kenneth M
KM
Reczek
Peter R
PR
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D017364:Collagenases / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D051379:Mice; D008811:Mice, Inbred DBA; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D012176:Retinoids / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C423184:BMS 189453; D002273:Carcinogens; D007375:Interleukin-1; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D013755:Tetradecanoylphorbol Acetate