Toward development of a potassium (K+)-based intra-articular injection for osteoarthritis treatment

Abstract

Osteoarthritis (OA) is characterized by a slow progression of cartilage erosion driven in part by a cascade of inflammatory mediators produced from an activated synovium and the cartilage itself. Chondrocytes lose their capacity to maintain a healthy cartilage extracellular matrix as they transition from an anabolic, healthy phenotype to a catabolic, hypertrophic phenotype. Activated synovial macrophages contribute to the chondrocyte phenotype shift and subsequent cartilage degradation through the secretion of pro-inflammatory molecules. Currently, there is not a single effective disease modifying treatment that can intervene in this degradative cascade. The goal of this work is to develop an intra-articular (IA) injection treatment that targets these two aberrant cell phenotypes through depolarization of the cells’ transmembrane potential (Vmem). Increasing the extracellular potassium (K+) concentration is a simple way to depolarize Vmem. In theory, a K+-based IA solution would be inexpensive, widely available, easy-to-implement, and able to alleviate long-term storage concerns associated with other potential treatments such as stem cells or protein-based pharmaceuticals.

This thesis focuses on initial, in vitro proof-of-concept studies designed to demonstrate the therapeutic potential a K+-based IA injection treatment for OA. Specifically, addition of K+ gluconate into culture media induces favorable changes in both osteoarthritic chondrocytes and interferon-gamma stimulated macrophages (M(IFN)). Furthermore, short-term stimulation (1 day) with K+ gluconate elicits prolonged beneficial responses in M(IFN) after 5 days despite the continued presence of IFN. The macrophage response noticed with K+ gluconate is not observed with either a clinically utilized IA injectable (methyl-prednisolone acetate - a corticosteroid) or a cell-based (human mesenchymal stem cell) injectable. Future work for this project will move towards in situ and in vivo studies.