Targeting Signaling Pathways with Small Molecules in Osteoarthritis

Abstract: “Targeting Signaling Pathways with Small Molecules in Osteoarthritis” One of today’s greatest needs in managing osteoarthritis (OA) is an intervention that stops or delays joint tissue destruction and progression to “joint failure”. The overall goal of this exploratory/developmental project is to use a novel high throughput small molecule screening (HTS) technology combined with CRISPR screening and target prioritization tools to identify signaling pathways and therapeutic targets for disease modification in OA. The pathobiological processes that promote OA result from activation of cell signaling pathways and subsequent changes in gene transcription mediated by a host of factors. The complexity of OA explains why a single target approach for disease modification has met with limited success. We propose that use of small molecules to target pathways that regulate expression of multiple OA mediators will represent a viable and more promising approach. We have established a robust cell-based high throughput functional screening (HTS) assay using normal human chondrocytes treated with a matrikine relevant to OA progression. We found this system to be a valid in vitro model of the OA chondrocyte phenotype that allows us to investigate multiple pathways and targets, providing a distinct advantage over single target analysis. Our aims are: Aim 1: Identify OA signaling pathways and potential therapeutic targets through high throughput cell-based compound screening, network analysis of genetic and genomic datasets, and CRISPR screening. Aim 2: Determine the ability of compounds that target prioritized pathways to restore the catabolic and anabolic balance in joint tissues. At the completion of the project, we expect to: 1) identify one or more new cell signaling pathways contributing to dysregulated catabolic and anabolic activity in OA joint tissues; 2) identify specific therapeutic targets within those pathways; and 3) discover small molecules for further testing in preclinical models of OA. These outcomes would serve as the basis for lead optimization and further development of disease-modifying drugs for OA in humans.