James J. Steinberg

Inhibition of cartilage breakdown by hydrocortisone in a tissue culture model of rheumatoid arthritis.

Bovine nasal cartilage discs cocultured with human rheumatoid synovial membrane or synovial-membrane-conditioned media release proteoglycan largely as a result of cartilage breakdown. We assessed the effects of hydrocortisone on proteoglycan distribution between cartilage and culture medium, and on cartilage breakdown expressed as the release of either proteoglycan or 35S-products from prelabelled discs. The presence of synovial membrane inhibited the capacity for net proteoglycan synthesis, preventing its accumulation in cartilage; this was little affected by hydrocortisone. The major response to pharmacological concentrations of hydrocortisone was suppression of both spontaneous and synovial-membrane-induced cartilage breakdown. The autolysis of synovial protein that normally occurred during culture was similarly prevented by comparable doses of corticosteroid. Changes in chromatographic distribution of the 35S-labelled degradation products released from cartilage conformed with a corticosteroid-induced inhibition of endogenous lysosomal or related proteinase activity. Additionally, inhibition of the early events in synovial membrane that are responsible for chondrocyte-mediated breakdown of cartilage may contribute significantly to the overall corticosteroid effect.

Dextran sulphate induced arthritis in rabbits.

Persistent effects of a short course of intra-articular dextran sulphate, dextrans, or chondroitin sulphate were examined in rabbit knees. Only dextran sulphate produced gross arthritis, associated with high synovial acid phosphatase and beta-glucuronidase activities. Synovial degradative capacity in synovium-cartilage cocultures was increased 2-fold by dextran sulphate and 1.5-fold by chondroitin sulphate treatments. Stimulation of cartilage breakdown in vitro paralleled the content of synovial marker enzyme at death of the animal, but the 2 responses could be dissociated.

Effect of steroid hormones on endotoxin-mediated cartilage degradation.

SummaryCartilage degradation is a characteristic feature of various types of human arthritis, notably rheumatoid arthritis and osteoarthritis. The influence of glucocorticoid and other steroid hormones on cartilage proteoglycan breakdown was examined in a model system in which breakdown is readily quantified by the release of proteoglycan from cultured bovine nasal cartilage discs. Endotoxin (bacterial lipopolysaccharides) treatment enhanced the depletion of cartilage proteoglycan by 2–3 fold. This was inhibited in a concentration-dependent manner by hydrocortisone (10−9 to 10−5M) or other glucocorticoid hormones (dexamethasone, prednisolone, cortisone). Inhibition required the continued presence of the steroid. Removal of hydrocortisone (3 × 10−7M) after 4 days from endotoxin-treated cultures resulted in the rapid restoration of an endotoxin response, so that proteoglycan release approached maximum levels during a second 4-day culture period. Other C-21 steroid hormones (progesterone, aldosterone) were also inhibitory at 10−5M, but testosterone and β-estradiol showed little influence on endotoxin action. Proteoglycan products of smaller average mol wt (Sepharose CL-2B chromatography), consistent with core protein cleavages, were released from endotoxin-treated cartilage. Cleavage was unaffected by β-estradiol, partially blocked by aldosterone and largely prevented by hydrocortisone administration.