FM-dye inhibition of Piezo2 relieves acute inflammatory and osteoarthritis knee pain in mice of both sexes

Abstract Musculoskeletal pain is a significant burden affecting billions of people with little progress in the development of pharmaceutical pain relief options. The mechanically-activated ion channel Piezo2 has been shown to play a role in mechanical sensitization; however there has been little progress in examining therapeutics that target this molecule. The goal of this study was to assess the effect of two FM-dyes, FM1-43 or FM4-64, in reducing acute inflammatory and osteoarthritis knee joint pain in mice of both sexes. In our acute model of Complete Freund’s adjuvant (CFA)-induced joint pain, mice intra-articularly injected with FM1-43 exhibited an attenuation of knee hyperalgesia 90 minutes following injection. In vivo calcium imaging of the dorsal root ganglion (DRG) also demonstrated a reduction in nociceptor responses to mechanical forces applied to the knee joint of CFA mice following FM-dye injection. Male and female WT mice subjected to partial medial meniscectomy (PMX) surgery as a model of osteoarthritis developed more severe knee hyperalgesia than nociceptor-specific Piezo2 conditional knock-out mice. Intra-articular injection of FM1-43 reduced both knee hyperalgesia and weight-bearing asymmetry in this model and had no effect in Piezo2 conditional knock-out mice. Finally, in mice with spontaneous osteoarthritis associated with aging, intra-articular injection of FM-dyes also reduced knee hyperalgesia. In conclusion, inhibiting Piezo2 genetically or pharmacologically was effective in reducing pain-related behaviors in mice of both sexes in the setting of inflammatory and osteoarthritis knee pain. These studies provide evidence of the therapeutic potential of targeting Piezo2 in musculoskeletal pain conditions.