Innate inflammation in osteoarthritis

骨关节炎的先天性炎症

• 批准号: 9351732
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351732
• 关键词: Address; Affect; Age; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Autophagocytosis; BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like; Biogenesis; Biological Markers; Biology; Biomechanics; Cartilage; Cells; Cellularity; Chondrocytes; Coupling; Degenerative polyarthritis; Development; Disease; Elderly; Excision; Failure; Feedback; Functional disorder; Funding; Gene Expression; Goals; Homeostasis; Human; Impairment; In Vitro; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Injury; Joints; Knee; Knee Osteoarthritis; Knock-out; Link; Maintenance; Mediating; Mediator of activation protein; Medical; Membrane Proteins; Mitochondria; Modeling; Molecular; Mus; Nuclear; Nucleosome Core Particle; Outcome; Outer Mitochondrial Membrane; PINK1 gene; Pathogenesis; Peptides; Phenotype; Polyubiquitination; Process; Proteins; Quality Control; Risk Factors; Role; Signal Transduction; Sorting - Cell Movement; Stress; System; Systems Biology; Testing; Translations; Trauma; Ubiquitin; Veterans; Work; aged; analog; arthropathies; articular cartilage; cartilage cell; cartilage degradation; disability; early onset; factor A; feeding; gain of function; humanin; improved; improved functioning; in vivo; injured; innovation; joint injury; middle age; mitochondrial dysfunction; mouse model; mtTF1 transcription factor; multicatalytic endopeptidase complex; normal aging; novel; novel marker; parkin gene/protein; response; response to injury; targeted treatment; tissue degeneration; transcription factor

Osteoarthritis (OA) is a major cause of disability in the USA, particularly so in veterans, who are disproportionately affected by aging and joint trauma. OA culminates in failure of the joint, which includes compromised cartilage chondrocyte differentiation and function, by mechanisms that are not completely understood. Because there is no disease-modifying medical therapy for OA, there is major unmet need to advance translation. Our long-term objective is to validate novel targets to limit OA cartilage failure, including processes that promote molecular innate inflammatory processes ("inflamm-aging"). A major obstacle in the field is that multiple homeostasis mechanisms are dysfunctional in OA chondrocytes, and we need to sort out which are the earliest, and central to the chondrocyte differentiation changes and viability loss. We have identified decreased mitochondrial mass, function, and biogenesis capacity in aging and OA knee chondrocytes, linked partly to deficiency of TFAM and other mitochondrial transcription factors. Our core hypothesis is that articular chondrocyte mitochondrial dysfunction is an early, pivotal, targetable, and reversible change in OA due to aging and biomechanical injury, and amplified by altered mitochondrial retrograde signaling. This includes decrease in the anti-inflammatory mitochondrial peptide humanin, causing effects on chondrocytes that we posit to be at least partly reversible in vitro using the humanin analog HNGF6A. Effective control of injury- and aging-associated tissue degeneration requires not only biogenesis but also maintenance of healthy mitochondria. In the novel, testable OA pathogenesis model that we hypothesize, chondrocyte mitochondrial damage is perpetuated, in large part, by feed-forward and feedback loops involving compromise in cell surveillance mechanisms that normally assure mitochondrial quality control. We specifically hypothesize the failure of chondrocyte mitophagy, via not only deficiency of the mitophagy “linchpin” BNIP3a, but also decreased proteasomal degradation of damaged polyubiquitinated outer mitochondrial membrane proteins, such as PINK1 and Parkin, by the ubiquitin proteasome system (UPS), which is essential for mitophagy. Our preliminary studies break substantial new ground by revealing markedly impaired UPS function in OA chondrocytes, including defective 20S proteasome core particle proteolytic activity, and accumulation of chondrocyte K48 polyubiquitinated proteins. We further identified that human knee OA chondrocytes have impaired assembly of the proteasome, a state that induces global outcomes of loss of chondrocytic differentiation, via diminished expression of the chondrocyte master transcription factor Sox9, and decreased matrix anabolic gene expression. For testing our integrative model of early, pivotal OA pathogenesis, innovation is applied by our bringing together of a particularly diverse investigative team, including collaborating experts in mitochondrial biology, autophagy and mitophagy, and in the UPS and profiling of cellular ubiquitylome signatures. We will employ our recently validated model of chondrocyte biomechanical injury, and carry out unique studies of human chondrocyte aging, via age-matched analyses of both normal and OA knee chondrocytes. Moreover, we address the problem of specifically testing the role of mitochondrial damage in OA of aging, by generating a chondrocyte-specific mouse model of TFAM knockout, which will be compared to normal mice in analyses for OA with aging in vivo. Completion of these studies will advance our long term goal of spurring translation in OA, by identifying novel OA chondrocyte biomarkers, and by pinpointing humanin and other novel, rational targets for potential development of medical disease-modifying OA therapies.

骨关节炎（OA）是美国残疾的主要原因，特别是退伍军人，他们是 不成比例地受到衰老和关节创伤的影响。OA最终导致关节失败，包括 受损的软骨软骨细胞分化和功能，通过不完全的机制， 明白由于OA没有改善疾病的药物治疗，因此存在主要未满足的需求， 提前翻译。我们的长期目标是验证限制OA软骨衰竭的新靶点，包括 促进分子先天炎症过程（“炎症-老化”）的过程。中的一大障碍 领域是，多种稳态机制在OA软骨细胞中功能失调，我们需要整理出 这是软骨细胞分化变化和活力丧失的最早和中心。我们有 在老化和OA膝关节中发现线粒体质量、功能和生物合成能力降低 软骨细胞，部分与TFAM和其他线粒体转录因子的缺乏有关。我们的核心 假设关节软骨细胞线粒体功能障碍是一种早期的、关键的、靶向的和可逆的 由于衰老和生物力学损伤而导致的OA变化，并因线粒体逆行改变而放大 发信号。这包括抗炎线粒体肽humanin的减少， 软骨细胞，我们证实，至少部分可逆的体外使用humanin类似物HNGF 6A。 有效控制损伤和衰老相关的组织变性不仅需要生物发生， 维持健康的线粒体。在我们假设的新的、可测试的OA发病机制模型中， 软骨细胞线粒体损伤在很大程度上是通过前馈和反馈回路持续存在的， 通常确保线粒体质量控制的细胞监视机制的妥协。我们特别 假设软骨细胞线粒体自噬的失败，不仅是由于线粒体自噬“关键”BNIP 3a的缺乏， 而且减少了受损的多泛素化线粒体外膜的蛋白酶体降解 蛋白质，如PINK 1和帕金，由泛素蛋白酶体系统（UPS），这是必不可少的 线粒体自噬 我们的初步研究通过揭示明显受损的UPS功能， OA软骨细胞，包括有缺陷的20 S蛋白酶体核心颗粒蛋白水解活性，以及 软骨细胞K48多聚泛素化蛋白。我们进一步确定，人膝关节OA软骨细胞具有 蛋白酶体组装受损，这种状态会导致软骨细胞丢失的全球结果 通过减少软骨细胞主转录因子Sox 9的表达， 基质合成代谢基因表达。为了测试我们早期关键OA发病机制的综合模型， 创新是通过我们汇集了一个特别多样化的调查团队，包括 在线粒体生物学，自噬和线粒体自噬，并在UPS和分析的合作专家， 细胞遍在蛋白组签名。我们将使用我们最近验证的软骨细胞生物力学模型 损伤，并进行人类软骨细胞老化的独特研究，通过年龄匹配的分析， 和OA膝关节软骨细胞。此外，我们解决了专门测试线粒体的作用的问题， 通过产生TFAM敲除的软骨细胞特异性小鼠模型， 与正常小鼠相比，在分析OA与体内老化。这些研究的完成将促进我们的 通过鉴定新的OA软骨细胞生物标志物， 精确定位人蛋白和其他新的，合理的目标，为潜在的发展，医疗疾病的改善， OA治疗。