Innate inflammation in osteoarthritis

骨关节炎的先天性炎症

基本信息

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
项目类别：
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

项目摘要

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，尤其是退伍军人，他们 OA 最终导致关节失效，其中包括软骨细胞分化和功能受损，机制不完全据了解，由于没有针对 OA 的疾病缓解药物疗法，因此存在重大未满足的需求。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”）的一个主要障碍。 OA 软骨细胞中多种稳态机制功能失调，我们需要弄清楚这是最早的，也是软骨细胞分化变化和活力丧失的核心。发现衰老和 OA 膝关节中线粒体质量、功能和生物发生能力下降软骨细胞，部分与 TFAM 和其他线粒体转录因子的缺乏有关。假设关节软骨细胞线粒体功能障碍是一种早期的、关键的、可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这包括抗炎线粒体肽人素的减少，从而对人体产生影响。我们假设使用人源类似物 HNGF6A 在体外至少部分可逆软骨细胞。有效控制损伤和衰老相关的组织退化不仅需要生物发生，还需要在我们勇敢的新型、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涉及以下因素的前馈和反馈循环而永久存在的：通常确保线粒体质量控制的细胞监视机制受到损害。不仅由于线粒体自噬“关键”BNIP3a 的缺陷，导致软骨细胞线粒体自噬失败，而且还减少了受损多泛素化线粒体外膜的蛋白酶体降解蛋白质，如 PINK1 和 Parkin，由泛素蛋白酶体系统 (UPS) 产生，该系统对于线粒体自噬。我们的初步研究揭示了 UPS 功能明显受损，从而开辟了重大新天地。 OA 软骨细胞，包括有缺陷的 20S 蛋白酶体核心颗粒蛋白水解活性和积累我们进一步鉴定出人类膝骨关节炎软骨细胞具有软骨细胞 K48 多聚泛素化蛋白。蛋白酶体组装受损，这种状态会导致软骨细胞丧失的整体结果分化，通过减少软骨细胞主转录因子 Sox9 的表达，并减少用于测试我们的早期关键 OA 发病机制的综合模型，我们汇集了一个特别多元化的调查团队来应用创新，其中包括线粒体生物学、自噬和线粒体自噬以及 UPS 和分析领域的合作专家我们将采用我们最近验证的软骨细胞生物力学模型。损伤，并通过对正常和正常软骨细胞的年龄匹配分析，对人类软骨细胞衰老进行独特的研究此外，我们还解决了专门测试线粒体作用的问题。通过生成 TFAM 敲除的软骨细胞特异性小鼠模型，该模型将与正常小鼠相比，对 OA 与衰老的体内分析进行比较，这些研究的完成将推进我们的研究。通过识别新的 OA 软骨细胞生物标志物以及通过确定护脑素和其他新颖、合理的目标，以促进医学疾病缓解的潜在发展 OA疗法。