Phlpp phosphatases in osteoarthritis

摘要 骨关节炎(OA)是一种慢性疼痛的疾病，也是世界各地导致残疾的主要原因。办公自动化是 以关节软骨恶化和其他关节病变为特征，包括半月板和韧带 损伤、滑膜炎、骨刺和关节疼痛。目前批准的治疗方法都不能改变疾病 通过减缓关节软骨退化或修复对关节组织的损伤而进展。我们确认了Phlpp 磷酸酶作为软骨再生和关节疼痛的可修改靶点。PHLPP1和Phlpp2是 在人骨性关节炎软骨中异常表达。PHLPP1基因敲除(KO)小鼠受到软骨保护 手术后的退化和疼痛相关行为(痛觉过敏和活动减少)会破坏关节的稳定 内侧半月板(DMM)，但PHLPP1条件性缺失的小鼠仅表达聚集蛋白(AGC) 细胞(PHLPP1 CKOAgc)只能防止软骨退化，而不能减少流动性。这些结果 提示PHLPP1在软骨细胞中的内在作用，以及PHLPP1/2在其他组织或细胞中的作用 在关节内。有趣的是，PHLPP1和Phlpp2的小分子抑制剂进一步减缓了软骨的生长 在PHLPP1 CKOAgc小鼠体内降解，并增加行动能力。PHLPP1/2抑制剂也刺激软骨细胞 抑制神经突起的生长和感觉神经元基因的表达 体外和体内。总之，这些数据表明PHLPP1/2在多种细胞类型/组织中的活性 关节参与了骨性关节炎的发病，而Phlpp2可能通过以下途径影响骨性关节炎的表型 通过调节关节神经支配和疼痛相关来补偿软骨和/或PHLPP1缺陷 行为。这个项目的总体目标是定义PHLPP1和Phlpp2如何调节软骨数量 和质量(即僵硬)以及PHLPP1/2失活如何促进损伤诱导的神经支配。具体的 目的：1)阐明PHLPP1和Phlpp2在关节损伤后关节软骨细胞中的作用；2) 确定PHLPP1和Phlpp2如何影响关节软骨的生物力学和结构特性 损伤后和整个衰老过程中的其他关节组织，以及3)确定感觉神经元中PHLPP1/2的活性 以及与骨性关节炎相关的疼痛行为。这些研究将提供关于两国之间关系的新信息 关节损伤，关节神经支配和疼痛。这样的洞察力将使急需的疾病的发展- 修改治疗骨性关节炎的药物。

ABSTRACT Osteoarthritis (OA) is a chronically painful condition and a leading cause of disability around the world. OA is characterized by articular cartilage deterioration and other joint pathologies including meniscus and ligament damage, synovitis, bone spurs and joint pain. None of the currently approved treatments alter disease progression by slowing articular cartilage degradation or repairing damage to joint tissues. We identified Phlpp phosphatases as modifiable targets for cartilage regeneration and joint pain. Phlpp1 and Phlpp2 are abnormally expressed in human OA cartilage. Phlpp1 knockout (KO) mice are protected from cartilage degradation and pain-related behaviors (allodynia and reduced mobility) after surgery that destabilizes the medial meniscus (DMM), but mice where Phlpp1 is conditionally depleted in just aggrecan (Agc)-expressing cells (Phlpp1 CKOAgc) are only protected from cartilage degradation, not reduced mobility. These results indicate an intrinsic role for Phlpp1 in chondrocytes, as well as a role for Phlpp1/2 in other tissues or cells within articulating joints. Of interest, small molecule inhibitors of Phlpp1 and Phlpp2 further slow cartilage degradation in Phlpp1 CKOAgc mice and increase mobility. Phlpp1/2 inhibitors also stimulate chondrocyte proliferation and matrix production and prevent neurite outgrowth and expression of sensory neuron genes in vitro and in vivo. Together these data indicate that Phlpp1/2 activity in multiple cell types/tissues within articulating joints contributes to OA pathogenesis and that Phlpp2 may contribute to OA phenotypes by compensating for Phlpp1 deficiency in cartilage and/or by regulating joint innervation and pain-related behaviors. The overall goals of this project are to define how Phlpp1 and Phlpp2 modulate cartilage quantity and quality (i.e. stiffness) and how Phlpp1/2 inactivation contributes to injury-induced innervation. The specific aims are to: 1) Elucidate the roles of Phlpp1 and Phlpp2 in articular chondrocytes following a joint injury, 2) Determine how Phlpp1 and Phlpp2 affect biomechanical and structural properties of articular cartilage and other joint tissues after injury and throughout aging, and 3) Define activities of Phlpp1/2 in sensory neurons and OA-associated pain behaviors. These studies will provide new information about the relationship between joint damage, joint innervation and pain. Such insights will enable the development of much needed disease- modifying drugs for osteoarthritis.