OBJECTIVE--To investigate the involvement of interleukin-1 (IL-1) in the induction or maintenance of the insulin-like growth factor 1 (IGF-1) non-responsive state of chondrocytes during experimental arthritis in mouse knee joints. METHODS--To characterise IGF-1 nonresponsiveness during arthritis, we measured chondrocyte proteoglycan (PG) synthesis by assaying incorporation of 35S-sulphate into mouse patellar cartilage, obtained from knee joints with experimentally induced arthritis and normal knee joints, cultured with IGF-1. We investigated whether suppressive mediators produced by the arthritic synovium or chondrocytes abolished the IGF-1 stimulation of normal cartilage, and used IL-1 primed cartilage to mimic the arthritic in vivo state. Specific inflammatory mediators responsible for the maintenance of the suppressed IGF-1 response were sought. We measured IGF-1 responsiveness in normal and arthritic patellae cultured with antibodies against tumour necrosis factor (TNF) or IL-1 alpha/beta, with IL-1 receptor antagonist (IL-1ra), and with several inhibitors of proteolytic enzymes or reactive oxygen species, and analysed the role of IL-1 in the development of IGF-1 non-responsiveness by studying IGF-1 responses in cartilage treated with IL-1 antibodies in vivo, at the onset of arthritis. RESULTS--Mediators from the surrounding tissue of both normal and arthritic cartilage suppressed chondrocyte IGF-1 responses. Priming the cartilage with IL-1 did not directly induce IGF-1 non-responsiveness, but enhanced the ability of suppressive mediators from synovium or chondrocytes to downregulate the IGF-1 responsive state. IL-1ra, IL-1 alpha/beta antibody, TNF antibody, or the inhibitors tested did not markedly improve the disturbed IGF-1 response, but treatment with anti-IL-1 at the onset of arthritis prevented the development of IGF-1 non-responsiveness. CONCLUSION--IL-1 alone does not induce IGF-1 non-responsiveness and is not critical in the maintenance of this phenomenon. However, IL-1 does appear to be an important cofactor in the generation of the IGF-1 non-responsive state.
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