Innate Inflammation in Osteoarthritis

骨关节炎的先天炎症

• 批准号: 8698319
• 负责人: Robert A. Terkeltaub
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698319
• 关键词: Age-Years; Aging; Alginates; Apoptosis; Apoptotic; Athletic; Back; Binding; Binding Proteins; Biological Markers; Biomechanics; Boxing; Cartilage; Catabolism; Cattle; Cells; Chondrocytes; Custom; Degenerative Disorder; Degenerative polyarthritis; Development; Diagnosis; Dimerization; Disease; Dissociation; Elderly; Endoribonucleases; Event; Extracellular Matrix; Financial cost; Foundations; GRP78 gene; GTP Binding; Guanine Nucleotides; Head; Healthcare; Healthcare Systems; Homeostasis; Human; Immune response; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Introns; Joints; Knee; Knee Osteoarthritis; Knock-out; Knockout Mice; Lead; Light; Mediating; Medical; Membrane Proteins; Messenger RNA; Military Personnel; Mission; Modeling; Molds; Molecular Chaperones; Molecular Conformation; Mus; Nucleotides; Organ Model; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Proteins; Protocols documentation; RNA Interference; RNA Splicing; Receptor Activation; Recombinants; Recovery; Regulation; Resolution; Role; Services; Severities; Site; Small Interfering RNA; Stress; Synovial Membrane; TLR2 gene; Testing; Time; Toll-like receptors; Training; Transcription Coactivator; Veterans; abstracting; adenylate kinase; arm; articular cartilage; autocrine; base; chronic pain; cytokine; cytotoxic; disability; endoribonuclease; extracellular; in vivo; joint injury; mutant; new therapeutic target; novel; paracrine; response; social; transglutaminase 2; waiver

DESCRIPTION (provided by applicant): Project summary/abstract: Osteoarthritis (OA) is associated with past biomechanical injury to cartilage and with aging. However, biomechanical injury and aging do not inevitably lead to OA. This proposal will focus on chondrocyte-centered innate inflammatory mechanisms in OA. We have characterized cartilage catabolism- promoting effects on chondrocytes for inflammation-mediated release of the multifunctional protein transglutaminase 2 (TG2). TG2 is abundant in the OA cartilage extracellular matrix and TG2 transamidation catalytic activity increases in aging cartilage. We observed that TG2 is a biomarker of OA severity, and we validated that global TG2 knockout is protective for instability-induced knee OA in mice. To pinpoint biomechanical injury and stress induced cartilage innate inflammatory responses that provide a foundation upon which OA is then triggered or accelerated, we will examine the linkage of TG2 release and XBP1 (X-box binding protein 1) activation in chondrocyte innate inflammation, proposed by us as a central switching mechanism for OA development and progression. XBP1 activation is specific to activation of ER stress, and successful resolution of ER stress promotes cell recovery and survival from injury. However, XBP1 activation also plays a central role in multiple organ models of innate inflammation, including via Toll-like receptor activation. We observe that biomechanical injury induces activation of ER stress in chondrocytes. Moreover, we detect active XBP1 increased in human knee OA chondrocytes. We also observe that cultured TG2 deficient chondrocytes have decreased XBP1 activation, but that extracellular TG2 induces XBP1 activation. Furthermore, we have generated cartilage-specific XBP1 knockout mice to probe for XBP1 function in chondrocytes. Here, we will test a hypothetical model in which TG2 and XBP1, by transducing and/or amplifying responses to biomechanical injury and oxidative stress, switch on chondrocyte innate inflammatory stress to promote OA development and progression. We specifically aim to: 1. Test the hypothesis that TG2 increases biomechanical injury-induced and oxidative stress-related catabolic and apoptotic responses of cultured chondrocytes mediated by HIF-2alpha activation and TG2 guanine nucleotide binding. 2. Test the hypothesis that TG2 increases injury and oxidative stress-induced catabolic and apoptotic responses of cultured chondrocytes critically mediated by XBP1 activation and decreased AMPK activity. 3. Test the hypothesis, in complementary studies in mice, that both cartilage-specific TG2 and XBP1 deficiency are protective against development and progression of OA. Completion of these studies will shed new light on the pathogenesis of OA related to biomechanical injury and aging, and identify potential new therapeutic targets.

描述（由申请人提供）： 项目摘要/摘要：骨关节炎（OA）与软骨和衰老的过去生物力学损伤有关。然而，生物力学损伤和衰老不可避免地导致OA。该提案将集中于OA中以软骨细胞为中心的先天炎症机制。我们表征了软骨分解代谢 - 促进对软骨细胞的影响，以促进多功能蛋白质转凝集酶2（TG2）的炎症介导的释放。 TG2在OA软骨外基质中很丰富，TG2转移催化活性在衰老软骨中增加。我们观察到TG2是OA严重程度的生物标志物，我们验证了全球TG2敲除对小鼠的不稳定性引起的膝关节OA保护性。为了查明生物力学损伤和压力引起的软骨先天炎症反应，这为OA随后触发或加速提供了基础，我们将研究TG2释放和XBP1和XBP1（X-box结合蛋白1）激活软骨细胞炎症的链接，并提出，AS AS AS AS AS ASS Switching机构OA的开发机构提出了OA的开发机构。 XBP1激活特定于ER应力的激活，而成功的ER应力分辨率促进了细胞的恢复和损伤的存活。然而，XBP1激活在多个先天炎症的器官模型中也起着核心作用，包括通过Toll样受体激活。我们观察到生物力学损伤会诱导软骨细胞中的ER应激激活。此外，我们检测到人膝膝骨软骨细胞中有效XBP1增加。我们还观察到培养的TG2缺乏软骨细胞降低了XBP1激活，但是细胞外TG2会诱导XBP1激活。此外，我们已经生成了软骨特异性XBP1基因敲除小鼠，以探测软骨细胞中XBP1功能。在这里，我们将通过转导和/或放大对生物力学损伤的反应和氧化应激的反应，转换软骨细胞先天炎症应激以促进OA的发育和进展，从而测试一个假设模型，其中TG2和XBP1通过转导和/或扩增反应。我们特别旨在：1。测试TG2增加生物力学损伤引起的和氧化应激相关的分解代谢和凋亡反应的培养软骨细胞和凋亡的反应，由HIF-2Alpha激活和TG2鸟嘌呤核苷酸结合介导。 2。检验的假设是TG2增加了培养的软骨细胞的损伤和氧化应激诱导的分解代谢和凋亡反应，这些软骨细胞严格介导了XBP1激活并降低AMPK活性。 3。在小鼠的互补研究中检验该假设，即软骨特异性TG2和XBP1缺乏症都可以防止OA的发育和进展。这些研究的完成将为与生物力学损伤和衰老相关的OA发病机理提供新的启示，并确定潜在的新治疗靶标。