PHLPP inhibition and Osteoarthritis-Associated Pain

摘要 骨关节炎(OA)是一种以关节软骨退化为特征的进行性和衰弱的疾病。 以及其他组织的病理变化，导致关节僵硬和疼痛。非手术治疗主要集中在 行为改变和疼痛缓解，但对控制伤害性感觉的分子通路知之甚少 在骨性关节炎的发病机制中。在这个项目中，我们将研究如何控制PHLPP磷酸酶的活性 在体内促进关节神经支配，在体外促进轴突伸展。 我们发现PHLPPs是软骨细胞再生和疼痛相关行为的抑制因子。PHLPP1和 PHLPP2存在于人和小鼠的感觉神经元中，在人的骨性关节炎软骨中异常表达。 在OA动物模型中，关节内注射PHLPP抑制剂可预防关节超敏反应和 软骨退化和关节组织感觉神经元神经支配减少(例如，软骨下骨， 骨膜)。PHLPP抑制剂抑制小、中型感觉神经元的生长和表达 神经递质和神经细丝的体外实验。该项目的目标是通过以下方式确定机制 哪种PHLPP磷酸酶小分子抑制剂可抑制骨性关节炎相关疼痛。中环 假说是PHLPP抑制剂可防止骨关节炎关节的神经支配并改变分子通路 控制感觉神经突起的延伸。我们将研究PHLPP抑制剂防止轴突形成的机制 用敏感的小鼠神经支配报告和人ipsc研究膝关节损伤后的伸展和关节疼痛 派生的感觉神经元模型系统。

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.