Anti-arthritic properties of FK506 on collagen-induced arthritis in rats.
OBJECTIVE
To determine the effect of FK506 (tacrolimus) on paw inflammation, TNF-alpha expression in joint, and bone and cartilage destruction in type II collagen-induced arthritis (CIA) model in rats.


METHODS
CIA was induced by immunization of female Lewis rats with an emulsion of bovine type II collagen and incomplete Freund's adjuvant. Paw inflammation was assessed by the increase in paw volume. Tumor necrosis factor (TNF) -alpha expression in hind knee joint was assessed by immunohistochemical analysis. Lesions of bone and cartilage were assessed on the basis of histological change in knee joint, radiographic analysis in hind paw, bone mineral density in femora and proteoglycan contents in the cartilage of femoral heads. FK506 at doses of 1, 1.8 and 3.2 mg/kg or its placebo formulation was orally administered to rats for 28 days from the day after immunization (n = 10). Effect of FK506 was compared with that of vehicle (distilled water).


RESULTS
FK506 at a dose of 1.8 mg/kg significantly suppressed paw swelling (p < 0.01) and histological change in knee joint (p < 0.05). Tumor necrosis factor (TNF)-alpha was mainly expressed in the region with a marked infiltration of inflammatory cells in the hind knee joint. FK506 (3.2 mg/kg) markedly reduced TNF-alpha expression. FK506 at a dose of 1.8 mg/kg suppressed radiographic changes in hind paw (p < 0.05) and also recovered the decrease in bone mineral density in the femora (p < 0.05). Proteoglycan contents in the cartilage of femoral heads were determined to evaluate the cartilage destruction more quantitatively and found to significantly decrease in CIA rats. FK506 at a dose of 1.8 mg/kg recovered the loss of proteoglycan contents (p < 0.01).


CONCLUSIONS
These results show that FK506 is effective in suppressing inflammation, TNF-alpha expression in joint, and damage to bone and cartilage in rat CIA, and may be useful in the treatment of rheumatoid arthritis.
Magari
K
K
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co, Ltd, 2-1-6, Yodogawa-ku 532-8514, Osaka, Japan.
Nishigaki
F
F
Sasakawa
T
T
Ogawa
T
T
Miyata
S
S
Ohkubo
Y
Y
Mutoh
S
S
Goto
T
T
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D007596:Joints / Q000187:drug effects / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D011509:Proteoglycans; D016559:Tacrolimus