A New Class of Osteoarthritis Therapeutic, Extracellular Matrix Protection Factor, Alters Cytokine Production in Chondrocytes

Articular cartilage damage leads to osteoarthritis (OA), a disease characterized by altered cartilage homeostasis. Several cellular elements including growth factors and proteases are involved in this pathology. Our lab has developed a new class of therapeutic, extracellular matrix protection factors (ECPFs), that protect cartilage from the devastation associated with OA. ECPF-1 targets the interaction between matrix metalloprotease 13 (MMP-13) and transforming growth factor b (TGF-b), but the cellular mechanism of ECPF-1 chondroprotection is unknown. It is well documented that inflammatory cytokines play a role in the pathology associated with OA, and that these molecules are regulated, in some part, by TGF-b biology. To test the downstream effects of blocking TGF-b activation on cytokine production, cultured chondrocytes from embryonic avian sterna were treated for 24 hours with ECPF-1 at 250nM, 2.5μM and 5.0μM concentrations and the production of the inflammatory cytokines, IL-1b and TNF-a, were monitored. Activated TGF-b was reduced and production of IL-1b and TNF-a were altered in response to ECPF-1 treatment including an unexpected increase in these cytokines following 5.0μM addition of ECPF-1. This biphasic effect of ECPF-1 indicates a duality to the protective therapeutic nature and overall mechanism of action of ECPF-1 in the protection of articular cartilage