Piezo2-mediated neuroplasticity in osteoarthritis

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Project Summary Despite the high prevalence of chronic pain and disability due to osteoarthritis (OA), there currently is no effective treatment available to stop progression or manage pain long term. Patients often report ceasing activities they found previously enjoyable or avoiding activities required for daily living due to the highly mechanosensitive nature of OA pain. Our understanding of OA has evolved from a wear and tear mindset to a complex disease state involving the immune and neurological systems, indeed there is an increase in immune cells and inflammatory mediators within the synovial fluid of humans and mice. Further in mice we see an increase in macrophages in knee innervating dorsal root ganglia (DRG); prevention of macrophage recruitment, by macrophage depletion or nociceptor silencing, has shown promise in reducing OA pain like behaviors. Interestingly, mice with Piezo2, a mechanically activated ion channel, knocked out from nociceptors demonstrate a reduction in pain behavior in two models of joint pain and are protected from joint swelling. Within animal modeling of OA there is evidence of altered neuroplasticity and sensitization that is attenuated by anti-nerve growth factor (NGF) therapy and through inhibition of Piezo2 suggesting an interplay between mechanical stimuli and inflammation in neuroplasticity. Unloading has been shown to silence mechanical signal transduction, decrease the expression of harmful proteases in the knee and is more effective in reducing synovitis than combination treatment with NSAIDs. However, no study has assessed the effect of unloading on pain associated neuroplasticity. We believe that mechanical signaling is a key player in macrophage recruitment and sensitization in OA, specifically through Piezo2. Therefore, our central hypothesis is: mechanical stimuli are necessary for joint neuroplasticity and inflammatory mechanical sensitization and by inhibiting mechanotransduction we will effectively reduce immune cell recruitment, abhorrent neuroplasticity and thus pain. Aim 1 will assess the effectiveness of inhibition of mechanical stimuli through Piezo2CKO in reducing immune cell recruitment to the knee and DRG. Aim 2 will tease apart the interplay of mechanical loading and inflammation in pain associated neuroplasticity by mechanically unloading mice to determine if altered neuroplasticity occurs under experimental pain conditions. This project will provide me the opportunity to learn new skills (flow cytometry, in vivo calcium imaging, sequencing) and develop novel techniques. I will also be given the opportunity to enhance skillsets required to achieve my career goals i.e. experimental design, scientific communication, critical thinking etc. Completion of the proposed project will increase our understanding of the interplay of mechanical information and immune cell dynamics in pain development and open the doors to routes of selective therapeutic intervention.