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Phlpp phosphatases in osteoarthritis

骨关节炎中的 Phlpp 磷酸酶

基本信息

批准号：
10707868
负责人：
Jennifer J Westendorf
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707868
关键词：
Adult Affect Afferent Neurons Age Age Months Aging Animal Model Arthralgia Articulation Atomic Force Microscopy Behavior Behavior Therapy Biological Assay Biomechanics Bone Spur Cartilage Cell Proliferation Cells Chondrocytes Compensation Coupled Data Degenerative polyarthritis Deterioration Development Disease Disease Progression Economic Burden Elasticity Enzymes Genes Goals Histology Histopathology Human In Vitro Injury Intra-Articular Injections Joints Knock-out Knockout Mice Measures Medial meniscus structure Meniscus structure of joint Messenger RNA Molecular Motion Mus Natural regeneration Neurites Neuronal Plasticity Neurons Neurotransmitters Operative Surgical Procedures Pain Painless Pathogenesis Pathologic Pathology Periosteum Pharmaceutical Preparations Phenotype Phosphoric Monoester Hydrolases Production Proliferating Property Reporter Risk Factors Role Saline Surface Synovial Membrane Synovitis Tamoxifen Testing Thick Tissues Weight-Bearing state Work aggrecan allodynia articular cartilage burden of illness cartilage degradation cartilage regeneration cartilage repair cell type chronic painful condition disability improved mobility in vivo inhibitor innovation insight interest joint injury ligament injury multidisciplinary nerve supply neurofilament novel therapeutics osteoarthritis pain overexpression pain behavior pain relief palliative preservation prevent regenerative small molecule inhibitor subchondral bone tissue regeneration tissue repair transcriptomics

项目摘要

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.

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。