EFFECTS OF METHOTREXATE ON NORMAL ARTICULAR-CARTILAGE IN-VITRO AND IN-VIVO

Objective-Methotrexate (MTX) has become the disease modifying drug of choice for the treatment of rheumatoid arthritis (RA). Direct effects of MTX on articular cartilage in vivo and in vitro were studied to det ermine possible adverse effects of the drug. Methods-For in vitro expe riments, adult bovine articular cartilage explants were cultured in th e presence of MTX (0 to 100 mu M), and effects on DNA and matrix metab olism were studied. For in vivo studies, 48 adult female rabbits were treated with MTX (30 mg/kg/week intramuscularly) or placebo, respectiv ely, for up to 12 weeks, and effects on the cartilage of the femoral c ondyles were assessed. Results-In vitro, MTX dose dependently increase d the uptake of [H-3]-thymidine, and decreased incorporation of [H-3]- d-uridine into chondrocytes with a half maximal effect at 0.03 mu M, s uggesting inhibition of thymidylate-synthetase activity by the drug. M TX also dose dependently reduced the proportion of chondrocytes in S-p hase, as determined by flow cytometry. MTX did not affect LDH release from chondrocytes or the proportion of viable cells, nor did it change the rate of protein synthesis, proteoglycan synthesis, proteoglycan b reakdown, or the hydrodynamic size of newly synthesised proteoglycans. In vivo, MTX did not appreciably affect proteoglycan synthesis of the chondrocytes, proteoglycan content of the cartilage matrix, density o f the chondrocyte population, or histological integrity of the cartila ge. Conclusions-The data suggest the absence of major adverse effects by MTX on articular cartilage proteoglycan metabolism. Chondrocyte DNA metabolism seems to be changed by MTX only in concentrations and expo sition periods clearly exceeding those found in synovial fluid of RA p atients receiving the commonly prescribed doses of the drug.