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.