Development of novel drugs for treating osteoarthritis and modulating the tumor microenvironment

Abstract

Part 1. Development of novel drugs for treating osteoarthritis Osteoarthritis (OA) is characterized by degradation of extracellular matrix macromolecules, inflammation and altered joint structure. We focused on zinc homeostasis in OA pathogenesis. Zinc is a crucial factor involving OA. Matrix metalloproteases (MMPs) are secreted proteins that require zinc for their proteolytic activities in extracellular matrix remodeling. Their degradation effects on the extracellular matrix play an important role in the progression of OA. A screening system was first designed by measuring zinc influx into the chondrocyte cell and the cell line is genetically modified into increased zinc influx by over-expressing the zinc importer, zip8. Two hit compounds were screened out and subjected to ex vivo gene expression analysis. Two hit compounds effectively decreased the downstream zinc-dependent matrix-degrading enzyme expression, which is a major catabolic factor of OA cartilage destruction. /// Part 2. Development of novel drugs for modulating the tumor microenvironment GAPDS is a novel compound segregating GAPDH glycolytic enzyme. In the previous study, it revealed that GAPDS has tubulin regulation effect, which may explain its anti-invasive properties. In this study, we focused on the GAPDS effect on tumor microenvironment, especially to cancer-associated fibroblast. We implemented tumor microenvironment in zebrafish animal model by co-injecting several cell types in TME. GAPDS attenuated cancer cell distribution in coinjeciton model. In addition, GAPDS drug changed fibroblast activation marker significantly in vitro. Taken together, our results demonstrate that GAPDS is a novel target for stromal based therapy to modulate pro-invasive molecular crosstalk within the tumor microenvironment.