Initial In Vitro Development of a Potassium-Based Intra-Articular Injection for Osteoarthritis

The long-term goal of this work is to develop a potassium (K⁺)-based intra-articular (IA) injection for osteoarthritis treatment. Within this context, the objectives of this study were to (1) demonstrate that hyperosmolar K⁺ solutions can suppress proinflammatory macrophage activation and (2) evaluate the therapeutic potential of a hyperosmolar K⁺ solution relative to a clinically utilized drug-based (methylprednisolone acetate [MPA]-a corticosteroid) or cell-based (human mesenchymal stem cell [hMSC]) IA injectable. A 3D in vitro model with poly(ethylene glycol) diacrylate hydrogels encapsulated with proinflammatory interferon-gamma (IFN)-stimulated macrophages (M(IFN)s) was utilized. Long-term changes in cell phenotype in response to short-term stimulation (i.e., mimicking an IA injection) were assessed following treatment with 80 mM K⁺ gluconate, hMSCs, or MPA. Addition of 80 mM K⁺ gluconate to culture media significantly reduced iNOS and TNF protein levels in M(IFN)s. Furthermore, short-term stimulation with K⁺ gluconate elicited a significant increase in the anti/proinflammatory cytokine profile in M(IFN)s, a response that is not noticed with either clinically utilized MPA or an hMSC injectable. Hyperosmolar K⁺ solutions are capable of attenuating proinflammatory macrophage activation. Moreover, when evaluated in an in vitro setting mimicking an IA injection, K⁺ performed significantly better than hMSCs or the corticosteroid MPA. Cumulatively, these results support further development and application of a K⁺-based IA injection toward osteoarthritis research.