SIGNAL-TRANSDUCTION THROUGH CHONDROCYTE INTEGRIN RECEPTORS INDUCES MATRIX METALLOPROTEINASE SYNTHESIS AND SYNERGIZES WITH INTERLEUKIN-1

Objective, To study the role of signal transduction via integrin recep tors in the production of metalloproteinase by rabbit articular chondr ocytes. Methods. Confluent, primary rabbit articular chondrocytes (RAG ) were incubated for 72 hours in the presence of interleukin-l (IL-1), Arg-Gly-Asp (RGD) peptide, or a combination of IL-1 and RGD peptide, Media were analyzed for stromelysin enzymatic activity using a H-3-lab eled transferrin substrate, and for stromelysin and collagenase protei n by Western analysis. Gelatinase activity was analyzed by gelatin zym ography. IL-l receptor antagonist (IL-1Ra) protein was used to determi ne the involvement of IL-1 in mediating the effects of RGD peptide, an d fluorescence-activated cell sorter analysis (FAGS) was used to exami ne the effect of IL-l on chondrocyte integrin subunit expression. Resu lts. RGD peptides induced chondrocyte synthesis of stromelysin, collag enase, and 92-kd gelatinase B, and increased synthesis of the constitu tively expressed 72-kd gelatinase A, Further studies focusing on strom elysin demonstrated that this up-regulation was concentration dependen t and that RGD peptides synergized with IL-1 in inducing stromelysin s ynthesis, RGD-induced stromelysin production was inhibited by the IL-1 Ra in a concentration-dependent manner, indicating that induction by R GD requires binding of IL-1 to its receptor, FAGS analysis of RAC show ed that IL-1 stimulation increased the expression of beta 1 and alpha v integrin subunits on the chondrocyte surface. Conclusion. Our data d emonstrate that signal transduction through chondrocyte integrin recep tors up-regulates metalloproteinase expression and that this is likely mediated through induction of IL-1, They also suggest that the bindin g of adhesion molecules to their chondrocyte integrin receptors reduce s the amount of IL-l required to induce stromelysin synthesis, Upregul ation of chondrocyte integrin expression by IL-1 may play a role in th e synergistic effects seen with a combination of IL-1 and RGD peptides , Since elevated levels of both IL-1 and adhesion molecules are presen t in rheumatoid arthritis and osteoarthritis synovial fluid, our data suggest that this interaction may be important in mediating the cartil age destruction accompanying these diseases.