PHLPP inhibition and Osteoarthritis-Associated Pain

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ABSTRACT Osteoarthritis (OA) is a progressive and debilitating disease characterized by deterioration of articular cartilage and pathologic changes to other tissues leading to joint stiffness and pain. Non-surgical treatments focus on behavior modifications and pain relief, but little is known about the molecular pathways controlling nociception during OA pathogenesis. In this project, we will examine how controlling the activity of PHLPP phosphatases contributes to joint innervation in vivo and neurite extension in vitro. We identified PHLPPs as suppressors of chondrocyte regeneration and pain-related behaviors. PHLPP1 and PHLPP2 are present in human and mouse sensory neurons and abnormally expressed in human OA cartilage. In an animal model of OA, intra-articular injection of PHLPP inhibitors prevented joint hypersensitivity and cartilage degradation and reduced sensory neuron innervation of joint tissues (e.g., subchondral bone, periosteum). PHLPP inhibitors suppressed outgrowth of small/medium sensory neurons and expression of neurotransmitters and neurofilaments in vitro. The goal of this project is to determine the mechanisms by which small molecule inhibitors of PHLPP phosphatases suppress OA-associated pain. The central hypothesis is that PHLPP inhibitors prevent innervation of osteoarthritic joints and alter molecular pathways controlling sensory neurite extension. We will study mechanisms by which PHLPP inhibitors prevent neurite extension and joint pain after knee injury with sensitive murine reporters of innervation and with human iPSC- derived sensory neuron model systems.