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Osteoarthrtis may be treated as an environmental ciliopathy

骨关节炎可以作为环境纤毛病来治疗

基本信息

批准号：
MR/L002876/1
负责人：
Martin Knight
金额：
$ 53.7万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL002876%2F1
关键词：
Osteoarthrtis may treated environmental ciliopathy

项目摘要

Osteoarthritis (OA) is a widespread, painful and debilitating condition that affects the synovial joints such as the hip and knee. The disease is associated with breakdown of the articular cartilage which, in healthy joints, provides a smooth, low friction load-bearing surface. This painful and debilitating condition affects over 8 million people in the UK alone and is a major burden to the health services and UK economy. Furthermore, this disease is likely to become more prevalent with the trend toward an aging population. Treatment of severe OA is restricted to total joint replacement, however, the current implants have a limited lifetime as well as problems associated with wear debris. It is therefore clear that an alternative approach for the treatment of cartilage degradation and OA is desperately needed. The cartilage is composed of living cells, a hundredth of a millimeter in diameter, which reside within an abundant extracellular matrix. This provides the tissue with its mechanical integrity which is critical to its function in the joint. The individual cartilage cells, called chondrocytes, each poses a single tiny hair-like projection called a primary cilium (plural cilia) which is involved in various cellular activities or signalling pathways. Our group and others have shown that primary cilia are important for cartilage development and health. Further studies indicate that OA is associated with changes in primary cilium dependent cellular signalling pathways and that this leads to degradation of the cartilage. Interestingly OA is also associated with changes in primary cilia length. We have recently found that environmental factors which predispose to OA, such as increased mechanical loading and the presence of inflammatory molecules, also alter cilia length and that this leads to changes in cilia function which may cause tissue degradation. We therefore aim to test the hypothesis that OA is associated with disruption of the joint environment causing changes in primary cilia structure and function leading to further destruction of the cartilage extracellular matrix. If this is found to be true it will open the way to novel therapeutic approaches for the treatment of OA through pharmaceutical manipulation of primary cilia structure and function. The work will involve testing of bovine cartilage cartilage cells as well as human cells obtained from patients undergoing total joint replacement surgery. This will allow us to determine the role of specific environmental regulation of primary cilia length on the function of the primary cilium and the subsequent degradation of the cartilage and progression of OA. In addition we will conduct a wide-spread screen of potential pharmaceutical molecules which regulate chondrocyte primary cilia length. We will then test to see if molecules which alter cilia length can be used to successfully reduce cartilage degradation. These tests will initially be conducted using both bovine and human cartilage tissue. However we will ultimately test the most promising therapeutic molecules using a well-established in vivo rat model of arthritis. In this way we will determine the efficacy of pharmaceutical manipulation of primary cilia in preventing cartilage degradation .Thus by the end of the project we will have identified the role of environmental regulation of primary cilia length in cartilage degradation and determined the efficacy of a totally novel treatment for OA in the form of pharmaceutical regulation of primary cilia structure and function.

骨关节炎（OA）是一种广泛的，疼痛和衰弱的疾病，影响滑膜关节，如髋关节和膝关节。这种疾病与关节软骨的破坏有关，在健康的关节中，关节软骨提供光滑、低摩擦的承重表面。这种痛苦和虚弱的状况仅在英国就影响了800多万人，是英国卫生服务和经济的主要负担。此外，随着人口老龄化的趋势，这种疾病可能会变得更加普遍。严重骨关节炎的治疗仅限于全关节置换术，然而，目前的植入物使用寿命有限，并且存在磨损碎片相关的问题。因此，很明显，迫切需要一种治疗软骨退化和OA的替代方法。软骨是由活细胞组成的，直径为百分之一毫米，存在于丰富的细胞外基质中。这为组织提供了其机械完整性，这对其在关节中的功能至关重要。单个软骨细胞称为软骨细胞，每个软骨细胞都有一个微小的毛发状突起，称为初级纤毛（复数纤毛），它参与各种细胞活动或信号传导途径。我们的小组和其他人已经表明初级纤毛对软骨发育和健康很重要。进一步的研究表明，骨性关节炎与初级纤毛依赖性细胞信号通路的改变有关，并导致软骨的退化。有趣的是，骨关节炎也与初级纤毛长度的变化有关。我们最近发现，易患OA的环境因素，如机械负荷的增加和炎症分子的存在，也会改变纤毛的长度，从而导致纤毛功能的改变，从而可能导致组织降解。因此，我们的目的是验证OA与关节环境破坏有关，导致初级纤毛结构和功能改变，从而进一步破坏软骨细胞外基质的假设。如果发现这是真的，它将为通过药物操纵初级纤毛结构和功能来治疗OA开辟新的治疗方法。这项工作将包括测试牛软骨细胞以及从接受全关节置换手术的患者身上获得的人类细胞。这将使我们能够确定特定环境对初级纤毛长度的调节对初级纤毛功能的作用，以及随后软骨的退化和OA的进展。此外，我们将对调节软骨细胞初级纤毛长度的潜在药物分子进行广泛筛选。然后，我们将测试改变纤毛长度的分子是否能成功地减少软骨退化。这些试验最初将使用牛和人的软骨组织进行。然而，我们最终将测试最有希望的治疗分子，使用一个完善的体内大鼠关节炎模型。通过这种方式，我们将确定药物操纵初级纤毛在防止软骨退化方面的功效。因此，在项目结束时，我们将确定环境调节初级纤毛长度在软骨降解中的作用，并确定以药物调节初级纤毛结构和功能的形式对OA进行全新治疗的有效性。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oncometabolite induced primary cilia loss in pheochromocytoma.

DOI：
10.1530/erc-18-0134
发表时间：
2019-01-01
期刊：
Endocrine-related cancer
影响因子：
3.9
作者：
O'Toole SM;Watson DS;Novoselova TV;Romano LEL;King PJ;Bradshaw TY;Thompson CL;Knight MM;Sharp TV;Barnes MR;Srirangalingam U;Drake WM;Chapple JP
通讯作者：
Chapple JP

Mechanobiology: From Molecular Sensing to Disease

力学生物学：从分子传感到疾病