Chondrocyte activation by interleukin-1: Synergism with fibroblast growth factor and phorbol myristate acetate

Exposure to synovial factors or purified interleukin-1 (IL-1) induces the production of prostaglandin E₂ (PGE₂) and the neutral proteinases (NP) collagenase, gelatinase and stromelysin by lapine articular chondrocytes. Having frequently found our partially purified synovial preparations to elicit this process of chondrocyte activation more strongly than recombinant IL-1, Phadke's report [1] of synergism between IL-1 and fibroblast growth factor (FGF) intrigued us. In our hands, basic FGF (1 ng/ml-1 μg/ml) did not activate chondrocytes but, in a dose-dependent manner, enhanced the production of PGE₂ and NP by chondrocytes exposed to IL-1α or IL-1β (1-10 U/ml). Further examination determined that the basic FGF was a better synergist than acidic FGF. In view of reports that FGF activates protein kinase C, we tested whether phorbol myristate acetate (PMA) could substitute for FGF as a synergist. Not only did it do so, but PMA alone (0.1 ng/ml-100 ng/ml), unlike FGF, provoked the production of PGE₂ by chondrocytes. The Ca²⁺ ionophore A23187 could not substitute for FGF in enhancing induction of the NP. Using a cDNA probe, we confirmed that the synergistic effects of both FGF and PMA upon IL-1 mediated collagenase induction, were associated with an increased abundance of collagenase mRNA.