INSULIN-LIKE GROWTH-FACTOR-I ACCELERATES RECOVERY OF ARTICULAR-CARTILAGE PROTEOGLYCAN SYNTHESIS IN CULTURE AFTER INHIBITION BY INTERLEUKIN-1

Interleukin 1 (IL-1) is a cytokine which induces cartilage proteoglyca n (PG) depletion by inhibiting PG synthesis and increasing PG breakdow n. Insulin-like growth factor I (IGF-I), in contrast, is known to prom ote matrix formation. We examined the effects of both mediators in a b ovine tissue culture model. IL-1 dose-dependently inhibited PG formati on of articular cartilage [half-maximal effect (EC50) at 4 ng/ml], whi le PG synthesis was increased by IGF-I (EC50 = 15 ng/ml). After inhibi tion of PG formation with IL-1 for 2 days and subsequent removal of fr ee IL-1, addition of IGF-I dose-dependently accelerated restoration of the original rate of synthesis with a half-maximal effect at 20 ng/ml and a maximal effect at 50 ng/ml. The IGF-I concentration required to elicit a half-maximal effect on cartilage PG synthesis remained const ant in the absence or presence of IL-1. We therefore conclude that inh ibition of cartilage PG synthesis by IL-1 is not effected by damage to the IGF receptor. Synovial fluid (SF) of 40 patients with rheumatoid arthritis (RA) was found to contain 64 +/- 6 ng IGF-I/ml (mean +/- SEM ). The reported effects of IGF-I in vitro therefore occurred at concen trations comparable to those present in joints in vivo. IL-1beta was d etectable (> 0.5 pg/ml) in 38 of 40 RA-SF samples (mean 28 +/- 6 pg/ml ). RA synovial tissue in culture released 330 +/- 112 pg IL-1beta x g tissue-1 x d-1, and this rate could be increased up to 70-fold by the addition of lipopolysaccharides (10 mug/ml). The observed accelerated recovery of cartilage PG synthesis by IGF-I after inhibition by IL-1 m ay be of relevance in rheumatic diseases like RA since IL-1 levels in RA-SF are known to vary considerably with time, and IGFs have been sho wn previously to be the most important promotors of cartilage PG synth esis in human SF.