Innate Inflammation in Osteoarthritis

骨关节炎的先天炎症

• 批准号: 8461078
• 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/8461078
• 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) 与过去的软骨生物力学损伤和衰老有关。然而，生物力学损伤和衰老并不必然导致骨关节炎。该提案将重点关注 OA 中以软骨细胞为中心的先天炎症机制。我们已经表征了软骨细胞对软骨细胞的软骨分解代谢促进作用，以促进炎症介导的多功能蛋白转谷氨酰胺酶 2 (TG2) 的释放。 TG2 在 OA 软骨细胞外基质中含量丰富，并且 TG2 转酰胺基催化活性在老化软骨中增加。我们观察到 TG2 是 OA 严重程度的生物标志物，并且我们验证了全局 TG2 敲除对于小鼠中不稳定引起的膝关节 OA 具有保护作用。为了查明生物力学损伤和应激诱导的软骨先天炎症反应为触发或加速 OA 奠定基础，我们将检查软骨细胞先天炎症中 TG2 释放和 XBP1（X-box 结合蛋白 1）激活之间的联系，我们提出将其作为 OA 发生和进展的中心切换机制。 XBP1 激活特定于 ER 应激激活，成功解决 ER 应激可促进细胞从损伤中恢复和存活。然而，XBP1 激活也在先天性炎症的多个器官模型中发挥着核心作用，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内质网应激的激活。此外，我们检测到人膝骨关节炎软骨细胞中活性 XBP1 增加。我们还观察到培养的 TG2 缺陷软骨细胞降低了 XBP1 激活，但细胞外 TG2 诱导 XBP1 激活。此外，我们还培育了软骨特异性 XBP1 敲除小鼠来探测软骨细胞中 XBP1 的功能。在这里，我们将测试一个假设模型，其中 TG2 和 XBP1 通过转导和/或放大对生物力学损伤和氧化应激的反应，开启软骨细胞先天炎症应激，以促进 OA 的发生和进展。我们的具体目标是： 1. 检验以下假设：TG2 增加由 HIF-2α 激活和 TG2 鸟嘌呤核苷酸结合介导的培养软骨细胞的生物力学损伤诱导和氧化应激相关的分解代谢和凋亡反应。 2. 检验以下假设：TG2 会增加损伤和氧化应激诱导的培养软骨细胞的分解代谢和凋亡反应，而这些反应主要由 XBP1 激活和降低的 AMPK 活性介导。 3. 在小鼠的补充研究中检验这一假设，即软骨特异性 TG2 和 XBP1 缺乏可预防 OA 的发生和进展。这些研究的完成将为与生物力学损伤和衰老相关的骨关节炎发病机制提供新的线索，并确定潜在的新治疗靶点。