INFLUENCE OF INTERLEUKIN-1-BETA, TUMOR-NECROSIS-FACTOR-ALPHA AND PROSTAGLANDIN E(2) ON CHONDROGENESIS AND CARTILAGE MATRIX BREAKDOWN IN-VITRO

Inflammatory mediators such as the cytokines interleukin-1 (IL-1) or ( TNF alpha), and prostaglandins [predominantly prostaglandin E(2) (PGE( 2))] are generally considered to be involved in the breakdown of carti lage matrix in chondrodestructive diseases, especially rheumatoid arth ritis and osteoarthritis. Their mode of action is not yet completely u nderstood. Blastemal cells or differentiated chondroblasts/chondrocyte s of limb buds from mouse embryos (day 12) in organoid cultures provid e an efficient system to investigate the mechanism of action of these substances. Using recombinant human IL-1 beta, TNF alpha and PGE(2) al one or together (in pairs) in this culture system, we found that none of these substances alone could affect chondrogenesis. TNF alpha, howe ver, when combined with IL-1 beta, proved to be the more potent cytoki ne causing a transformation of embryonal chondrogenic cells into fibro blast-like cells and thus inhibiting the expression of the cartilage c ell phenotype. This might be due to inhibition of both the morphogenet ic and cytodifferentiation phases of chondrogenesis. The well-known sy nergistic interaction between both cytokines seems to be phase limited and may not occur in the postchondrogenesis phase. In addition, our r esults showed that TNF alpha alone or combined with PGE(2) caused a ma rked breakdown of the cartilage matrix. These in vitro findings might be useful to elucidate the complexity of interactions between differen t cytokines and PGE(2) involved in cartilage destruction processes in vivo.