Cartilage Innate Immunity in Osteoarthritis

骨关节炎中的软骨先天免疫

• 批准号: 7636658
• 负责人: RU BRYAN
• 金额: $ 35.1万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636658
• 关键词: Adaptor Signaling Protein; Age; Aging; CD44 Antigens; CD44 gene; Cartilage; Catabolism; Chondrocytes; Data; Degenerative polyarthritis; Disease; Foundations; GAG Gene; Generations; HMGB1 gene; Hyaluronan; Hyaluronidase; Hypertrophy; Immune; Immune System Diseases; Immune response; In Situ; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 Receptors; Isoenzymes; Joints; Knee; Knee Osteoarthritis; Knock-out; Ligands; Matrix Metalloproteinases; Medial; Mediating; Mediator of activation protein; Modeling; Modification; Molecular Weight; Mus; Natural Immunity; Nitric Oxide; Oligosaccharides; Operative Surgical Procedures; Pathogenesis; Pattern; Pharmaceutical Preparations; Procedures; Production; Proteoglycan; Reaction; Receptor Signaling; Recruitment Activity; Role; Shapes; Signal Transduction; Stromelysin 1; Synovial Membrane; Synovitis; TLR2 gene; TLR4 gene; Testing; Toll-like receptors; Transducers; Urate; Work; aggrecanase; anakinra; arthropathies; base; cartilage development; chemokine; collagenase 3; collateral ligament; cytokine; in vitro Model; in vivo; insight; microbial; novel; programs; protective effect; public health relevance; receptor; receptor for advanced glycation endproducts; repaired; response; single molecule; therapeutic target

DESCRIPTION (provided by applicant): Primitive Toll-like receptor (TLR)-mediated innate immune responses trigger and shape many inflammatory and immune disorders. IL-1 induces TLR2 and TLR4 in chondrocytes and both TLRs are increased in OA cartilage in situ. Moreover, microbial TLR2 and TLR4 ligands stimulate catabolic responses in chondrocytes. Our preliminary data reveal that the shared TLR and IL-1 receptor adaptor protein MyD88 (but not soluble IL-1 receptor antagonist) blunts all inflammation-induced catabolic and differentiation responses tested in cartilage explants and cultured chondrocytes. We further observe that TLR2, TLR4 double knockout (TLR2/4 dKO) mouse cartilage explants and chondrocytes retain IL-1 responsiveness, but lose responsiveness to low molecular weight hyaluronan oligosaccharides (LMW-HA) and HMGB1, two endogenous TLR2 and TLR4 ligands present in OA joints. In addition, TLR2/4 dKO mouse chondrocytes lose the capacity to mount a catabolic response in chondrocytes with increased expression of not only hyaluronidase-2 which catalyzes LMW-HA formation but also HMGB1. The central and translational hypothesis of this proposal is that inhibition of both TLR2 and TLR4 signaling is chondroprotective both in vitro and in vivo and offers novel means to develop disease-modifying OA therapy. We will perform in vitro studies on responses of cartilage explants and chondrocytes to LMW-HA and HMGB1 to determine how TLR2 and TLR4 signaling promotes chondrocyte hypertrophy and cartilage catabolism using not only MyD88, but also TIRAP/Mal which is selectively required for TLR2 and TLR4 signaling. We will also perform in vivo studies using a surgical instability-induced knee OA model to assess if OA progression is suppressed by dual knockout of TLR2 and TLR4, and alternatively by single knockout of TIRAP/Mal, and if knockout of MyD88 has superior protective effects than knockout of IL-1 receptor for OA suppression. Completion of these studies will provide new insights into how innate immune inflammatory responses in cartilage promote OA progression and provide at least one potentially druggable target for effective OA disease modification. Relevance: Osteoarthritis (OA) is the most common joint disease related to aging. Progression of OA is promoted by low- grade inflammation in cartilage. Interleukin-1 (IL-1), an inflammatory mediator, promotes the progression of OA, but results have been incomplete for suppression of OA via IL-1 inhibition. There is a pressing need to identify mediators beyond IL-1 that drive OA progression, in order to develop true and effective disease modifying treatment of this disease. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) is the most common joint disease related to aging. Progression of OA is promoted by low-grade inflammation in cartilage. There is a pressing need to develop effective disease modifying treatment for OA. TLR2/4 innate immune signaling in the joint represents a novel target for OA.

描述（由申请人提供）：原始Toll样受体（TLR）介导的先天免疫反应触发并形成许多炎症和免疫疾病。 IL-1 诱导软骨细胞中的 TLR2 和 TLR4，并且这两种 TLR 在 OA 软骨中均增加。此外，微生物 TLR2 和 TLR4 配体刺激软骨细胞的分解代谢反应。我们的初步数据表明，共享的 TLR 和 IL-1 受体衔接蛋白 MyD88（但不是可溶性 IL-1 受体拮抗剂）会减弱在软骨外植体和培养软骨细胞中测试的所有炎症诱导的分解代谢和分化反应。我们进一步观察到 TLR2、TLR4 双敲除 (TLR2/4 dKO) 小鼠软骨外植体和软骨细胞保留了 IL-1 反应性，但失去了对低分子量透明质酸寡糖 (LMW-HA) 和 HMGB1（存在两种内源性 TLR2 和 TLR4 配体）的反应性在 OA 关节中。此外，TLR2/4 dKO小鼠软骨细胞失去了在软骨细胞中启动分解代谢反应的能力，不仅催化LMW-HA形成的透明质酸酶-2的表达增加，而且HMGB1的表达增加。该提议的核心转化假设是，抑制 TLR2 和 TLR4 信号传导在体外和体内均具有软骨保护作用，并为开发缓解疾病的 OA 疗法提供了新方法。我们将对软骨外植体和软骨细胞对 LMW-HA 和 HMGB1 的反应进行体外研究，以确定 TLR2 和 TLR4 信号如何促进软骨细胞肥大和软骨分解代谢，不仅使用 MyD88，还使用 ​​TLR2 和 TLR4 选择性需要的 TIRAP/Mal发信号。我们还将使用手术不稳定引起的膝关节 OA 模型进行体内研究，以评估 TLR2 和 TLR4 的双重敲除或 TIRAP/Mal 的单敲除是否可以抑制 OA 进展，以及 MyD88 的敲除是否具有卓越的保护作用比敲除 IL-1 受体来抑制 OA 更有效。这些研究的完成将为了解软骨中的先天免疫炎症反应如何促进 OA 进展提供新的见解，并为有效缓解 OA 疾病提供至少一个潜在的药物靶标。相关性：骨关节炎（OA）是与衰老相关的最常见的关节疾病。软骨中的低度炎症会促进 OA 的进展。白细胞介素-1 (IL-1) 是一种炎症介质，可促进 OA 的进展，但通过抑制 IL-1 来抑制 OA 的结果并不完整。迫切需要确定除 IL-1 之外驱动 OA 进展的介质，以便开发出真正有效的疾病缓解疗法。公共卫生相关性：骨关节炎 (OA) 是与衰老相关的最常见的关节疾病。软骨中的低度炎症会促进 OA 的进展。迫切需要开发有效的 OA 疾病缓解疗法。关节中的 TLR2/4 先天免疫信号代表了 OA 的新靶点。