EGFR signaling in osteoarthritis and treatment

骨关节炎中的 EGFR 信号传导及其治疗

• 批准号: 10417220
• 负责人: Ling Qin
• 金额: $ 45.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417220
• 关键词: Adult; Age-Years; Aging; Animal Model; Animals; Arthralgia; Attenuated; Biology; Bovine Cartilage; CREB1 gene; Cartilage; Cells; Chondrocytes; DTR gene; Data; Degenerative polyarthritis; Development; Disease; Elderly; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Gefitinib; General Population; Genes; Growth Factor; Health; Histology; Homeostasis; Hypertrophy; Joints; Knee; Knee Osteoarthritis; Knowledge; Life; Ligands; Lubrication; Mechanics; Mediating; Modeling; Molecular; Mus; Operative Surgical Procedures; Pain; Pathogenesis; Pathway interactions; Penetration; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prevalence; Proteoglycan; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Resolution; Role; Sclerosis; Series; Signal Pathway; Somatotropin; Structure; Surface; Testing; Therapeutic Effect; Transforming Growth Factor alpha; Translating; age related; aggrecan; arthropathies; articular cartilage; behavior test; cartilage degradation; clinically relevant; design; disability; experimental study; gain of function; genetic approach; genetic manipulation; improved; knock-down; loss of function; mechanical properties; mouse model; nanoparticle; novel; novel therapeutic intervention; overexpression; prevent; repaired; response; subchondral bone

Project Summary Osteoarthritis (OA) is a classic age-related disorder and the most common cause ofpain and disability in the elderly. It is primarily characterized by the progressive destruction of articular cartilage. This past decade has witnessed significant advances in deciphering the basic mechanisms by which OA develops. However, to date, no disease modifying drug therapy is available for preventing OA development and repairing the degenerative cartilage. The uppermost superficial zone of articular cartilage is the first line of defense against OA initiation. We recently found that epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, is expressed abundantly throughout the articular cartilage with its active form (p-EGFR) predominantly located in the superficial zone. Interestingly, at the onset of OA, p-EGFR amount, along with two major EGFR ligands (TGFα and HBEGF), were markedly attenuated while the amount of Mig6, a negative inhibitor of EGFR, was enhanced, suggesting a potential role for EGFR signaling pathway in cartilage homeostasis and diseases. Using a series of mouse models with deficient or overactivated EGFR activity by genetic manipulation of Egfr and Mig6 genes, we and others have demonstrated that EGFR signaling is critical for maintaining the number and mechanical properties of superficial chondrocytes, suppressing their hypertrophy, promoting proteoglycan 4 (Prg4) expression, and stimulating surface lubrication function. Most strikingly, in aging- and surgery-induced OA models, mice with chondrocyte-specific (Col2-Cre) EGFR deficiency developed the most severe OA phenotypes, including a complete loss of articular cartilage, subchondral bone sclerosis, and escalated joint pain. Hence, we hypothesize that EGFR signaling is essential for maintaining the structure and function of the superficial layer in the articular cartilage and thus, can be targeted for OA treatment. Our objectives are to understand the role of this novel signaling pathway in articular cartilage homeostasis and diseases, and to seek approaches targeting this pathway for OA treatment. To achieve these, we will perform the following aims: 1) determine the temporal role of EGFR signaling in OA pathogenesis; 2) elucidate the mechanisms of the protective action of EGFR on articular cartilage; 3) investigate whether EGFR signaling is a promising target for OA treatment. Complementary genetic approaches, such as EGFR vs Mig6, loss of function vs gain of function, and aggrecan-CreER vs Prg4-CreER, will be used throughout the proposal. Moreover, we have designed and synthesized TGFα-conjugated nanoparticles with prolonged retention and penetration abilities in knee cartilage. A proof-of-principal experiment will be performed to examine its therapeutic effects on cartilage degeneration at different OA stages. This proposal will uncover critical EGFR actions in knee articular cartilage and provide crucial evidence for targeting this novel pathway in OA therapies. Once successfully accomplished, this project could be quickly translated into large animal OA models followed by clinically relevant applications that would eventually improve the health and well-being of the general public.

项目概要 骨关节炎（OA）是一种典型的与年龄相关的疾病，也是老年人疼痛和残疾的最常见原因。 这 老年。 其主要特征是关节软骨的进行性破坏。过去十年 在破译 OA 发展的基本机制方面已经取得了重大进展。然而，为了 迄今为止，尚无可用于预防 OA 发展和修复骨关节炎的疾病缓解药物疗法。 退行性软骨。关节软骨最上面的浅层区域是抵御关节损伤的第一道防线 OA启动。我们最近发现表皮生长因子受体（EGFR）是一种酪氨酸激酶受体， 在整个关节软骨中大量表达，其活性形式 (p-EGFR) 主要位于 表面区域。有趣的是，在 OA 发作时，p-EGFR 含量以及两种主要 EGFR 配体 （TGFα 和 HBEGF）显着减弱，而 EGFR 阴性抑制剂 Mig6 的量则显着减弱。 增强，表明 EGFR 信号通路在软骨稳态和疾病中具有潜在作用。 通过对 Egfr 进行基因操作，使用一系列 EGFR 活性缺陷或过度激活的小鼠模型 和 Mig6 基因，我们和其他人已经证明 EGFR 信号传导对于维持数量至关重要 和表面软骨细胞的机械特性，抑制其肥大，促进蛋白聚糖 4(Prg4)表达，并刺激表面润滑功能。最引人注目的是，在衰老和手术引起的 OA 模型中，软骨细胞特异性 (Col2-Cre) EGFR 缺陷的小鼠出现最严重的 OA 表型，包括关节软骨完全丧失、软骨下骨硬化和关节升级 疼痛。因此，我们假设 EGFR 信号传导对于维持细胞的结构和功能至关重要。 关节软骨的表层，因此可以作为 OA 治疗的目标。我们的目标是 了解这种新的信号通路在关节软骨稳态和疾病中的作用，并 寻找针对这一途径的 OA 治疗方法。为了实现这些，我们将执行以下操作 目标：1) 确定 EGFR 信号传导在 OA 发病机制中的时间作用； 2）阐明机制 EGFR对关节软骨的保护作用； 3) 研究EGFR信号传导是否有前途 OA治疗的目标。互补遗传方法，例如 EGFR 与 Mig6、功能丧失与功能增强 of function, and aggrecan-CreER vs Prg4-CreER, will be used throughout the proposal.此外，我们还有 设计并合成了具有延长保留和渗透能力的 TGFα 缀合纳米颗粒 膝盖软骨。将进行原理验证实验来检查其对软骨的治疗效果 degeneration at different OA stages.该提案将揭示 EGFR 在膝关节软骨中的关键作用 并为 OA 治疗中针对这一新途径提供重要证据。一旦成功 完成后，该项目可以快速转化为大型动物 OA 模型，随后进行临床 最终将改善公众健康和福祉的相关应用程序。