EGFR signaling in osteoarthritis and treatment

骨关节炎中的 EGFR 信号传导及其治疗

• 批准号: 10701673
• 负责人: Ling Qin
• 金额: $ 44.28万
• 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/10701673
• 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.

项目摘要 骨关节炎是一种典型的与年龄相关的疾病，也是导致疼痛和残疾的最常见原因 这个 老年人。 其主要特征是关节软骨的进行性破坏。过去的十年 在破译开放式获取发展的基本机制方面取得了重大进展。然而，为了 到目前为止，还没有疾病修饰药物疗法可用于预防骨性关节炎的发展和修复 退变的软骨。关节软骨最上面的表面区是抵御 办公自动化入门。我们最近发现，表皮生长因子受体(EGFR)，一种酪氨酸激酶受体，是一种 在关节软骨中大量表达，其活性形式(p-EGFR)主要位于 表面区。有趣的是，在OA开始时，p-EGFR与两个主要的EGFR配体一起 (转化生长因子α和血管内皮细胞生长因子)的表达明显减弱，而表皮生长因子受体的负向抑制因子Mig6的量则明显减少。 增强，提示EGFR信号通路在软骨内稳态和疾病中可能发挥作用。 利用EGFR基因操作建立一系列EGFR活性低下或过度激活的小鼠模型 和Mig6基因，我们和其他人已经证明了EGFR信号对维持这一数量至关重要 和浅层软骨细胞的机械性能，抑制其肥大，促进蛋白多糖 4(Prg4)的表达，并具有刺激表面润滑作用。最引人注目的是，在衰老和手术诱导的 在骨性关节炎模型中，软骨细胞特异性(COL2-CRE)EGFR缺乏的小鼠发生最严重的骨性关节炎 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信号对维持细胞的结构和功能是必不可少的。 关节软骨中的浅层，因此，可以作为治疗OA的靶点。我们的目标是 了解这一新的信号通路在关节软骨内稳态和疾病中的作用，并 寻找针对这一途径的治疗OA的方法。为了实现这些目标，我们将执行以下操作 目的：1)确定EGFR信号在骨性关节炎发病机制中的时间作用；2)阐明骨性关节炎的发病机制 EGFR对关节软骨的保护作用；3)研究EGFR信号转导是否有前景 骨性关节炎治疗的靶点。互补遗传方法，如EGFR与Mig6、功能丧失与获得 功能，以及aggrecan-Creer与Prg4-Creer，将在整个提案中使用。此外，我们有 设计合成具有长时间滞留和穿透能力的转化生长因子α偶联纳米粒 膝关节软骨。将进行一项主要实验，以检验其对软骨的治疗效果。 退行性变在不同的骨性关节炎阶段。这项提案将揭示膝关节软骨中关键的EGFR作用。 并为在骨性关节炎治疗中靶向这一新途径提供了重要证据。一旦成功 该项目完成后，可以迅速转化为大型动物骨性关节炎模型，随后在临床上 相关应用，最终将改善公众的健康和福祉。