A small lipidated peptide targeting Na V 1.8 channels attenuates osteoarthritic pain behavior and prevents bone erosion
Abstract
Abstract Chronic pain is a major concern for patients with osteoarthritis (OA). Current treatments for OA-related pain often fail and may worsen the disease. The sodium channel subtype Na V 1.8 has emerged as a potential target for treating pain, leading to the development of Na V 1.8 inhibitors in clinical trials. We previously identified Magi-1, a WW domain-containing scaffold protein, as a regulator of Na V 1.8 at the plasma membrane of nociceptive neurons. Disrupting the interaction between Na V 1.8 and Magi-1 facilitated channel degradation in neurons, reducing pain behavior in multiple animal models. In this study, we investigated the impact of disrupting Na V 1.8 scaffolding on an animal model of OA pain using genetic and pharmacological approaches. Genetic Magi-1 knockdown effectively attenuated established OA pain in mice. Pharmacological targeting of the Na V 1.8-Magi-1 interaction in rats with a lipidated Na V 1.8 WW binding domain decoy peptide inhibited pain behavior for multiple weeks. MicroCT imaging revealed minimal alterations in subchondral bone remodeling in animals injected with the lipidated decoy peptide compared to those receiving scrambled peptide-control animals. This suggested that the Na V 1.8 peptidomimetic not only alleviated OA pain but also delayed joint degeneration. Our preclinical studies indicate that intraarticular injection of lipidated peptides capable of disrupting ion channel scaffolding in neurons can provide effective and sustained…
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