Cellular and Molecular Pathogenesis of Osteoarthritis

骨关节炎的细胞和分子发病机制

• 批准号: MR/W018950/1
• 负责人: John Bassett
• 金额: $ 111.27万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW018950%2F1
• 关键词: Cellular; Molecular; Pathogenesis; Osteoarthritis

RESEARCH CONTEXTOsteoarthritis is the leading cause of pain and disability. Its incidence has increased 50% in the last 30 years and it now affects more than 500 million people worldwide. 15% of the UK population suffer from osteoarthritis with an economic cost of £14.8 billion per annum. Despite the enormous personal, economic, and societal toll, osteoarthritis remains a generally neglected disease and a Lancet Commission has been established recently to address this problem directly. Osteoarthritis causes progressive cartilage wear and tear and failure of normal tissue repair that ultimately results in joint destruction. Understanding how osteoarthritis begins and progresses is limited because the joint is a complex structure consisting of different tissues and cell types, many of which are difficult to examine. Studies in humans are complicated by inclusion of patients of differing age, sex, ethnicity and aetiology. They also lack critical comparative information from normal joints as only tissue obtained at joint replacement for end-stage disease can be investigated. Thus, human studies cannot establish the causal relationships that connect changes in gene expression with mechanisms of disease. Accordingly, the only treatment for osteoarthritis is joint replacement and no drugs are available that can prevent disease onset or progression. A new and unbiased approach that uses a well-established and validated osteoarthritis disease model is now required to advance the field and address this critical unmet need.AIMS and OBJECTIVESWe hypothesise that tissue specific patterns of gene expression (spatial transcriptomics) obtained from the mouse knee joint during the onset and progression of disease will identify the key target cells, genes, major pathways and signalling networks that define osteoarthritis. AIM 1. Undertake detailed imaging and tissue specific spatial transcriptomics of knee joints from normal, aged and osteoarthritic mice.AIM 2. Prioritise key genes and signalling pathways that underpin the onset and progression of osteoarthritis.We recently identified severe early onset osteoarthritis in mice lacking one of the two copies of the Pitx1 gene. Thus, in Aim 3 we will establish the role of PITX1 in osteoarthritis and determine its mechanism of action in cartilage.AIM 3. Define the role of Pitx1 in the onset and progression of osteoarthritis in vivo.APPLICATIONS and BENEFITSThe studies in Aim 1 will: (i) define a cellular and molecular atlas of the knee joint and (ii) determine the sequential changes in the cellular and molecular programmes that occur during disease onset and progression. The studies in Aim 2 will: (i) integrate diverse and complementary mouse and human data sets and (ii) prioritise and validate the critical and tractable conserved genes and major signalling pathways involved in the onset and progression of osteoarthritis. The studies in Aim 3 will: (i) define the key target genes and downstream signalling pathways that are perturbed in articular cartilage following deletion of Pitx1 and (ii) provide an osteoarthritis disease model in which to determine the tractability and therapeutic potential of targeting PITX1 signalling.Overall, these studies will provide a new and detailed understanding of the cellular and molecular basis of osteoarthritis and identify novel drug targets for the prevention and treatment of this common and debilitating, yet neglected disease.

研究背景骨关节炎是疼痛和残疾的主要原因。它的发病率在过去30年中增加了50%，现在影响了全世界5亿多人。15%的英国人口患有骨关节炎，每年的经济成本为148亿英镑。尽管巨大的个人，经济和社会代价，骨关节炎仍然是一个普遍被忽视的疾病，最近成立了一个柳叶刀委员会来直接解决这个问题。骨关节炎会导致进行性软骨磨损和正常组织修复失败，最终导致关节破坏。了解骨关节炎如何开始和发展是有限的，因为关节是一个复杂的结构，由不同的组织和细胞类型组成，其中许多很难检查。人类研究因纳入不同年龄、性别、种族和病因的患者而变得复杂。他们还缺乏来自正常关节的关键比较信息，因为只能研究终末期疾病关节置换术中获得的组织。因此，人类研究无法建立将基因表达变化与疾病机制联系起来的因果关系。因此，骨关节炎的唯一治疗方法是关节置换术，并且没有可以预防疾病发作或进展的药物。现在需要一种新的、无偏见的方法，使用一种成熟的、经验证的骨关节炎疾病模型来推进该领域，并解决这一关键的未满足的需求。（空间转录组学）将鉴定在疾病发作和进展期间从小鼠膝关节获得的关键靶细胞，基因，定义骨关节炎的主要途径和信号网络。AIM 1.对正常、老年和骨关节炎小鼠膝关节进行详细的成像和组织特异性空间转录组学研究。我们最近在缺乏Pitx1基因的小鼠中发现了严重的早发性骨关节炎。因此，在目的3中，我们将建立PITX1在骨关节炎中的作用，并确定其在软骨中的作用机制。定义Pitx1在骨关节炎的发病和进展中的作用invivo.APPLICATIONS和BENEFITSThe目标1中的研究将：（i）定义膝关节的细胞和分子图谱，以及（ii）确定在疾病发病和进展期间发生的细胞和分子程序的顺序变化。目标2中的研究将：（i）整合不同和互补的小鼠和人类数据集，（ii）优先考虑并验证参与骨关节炎发作和进展的关键和易处理的保守基因和主要信号通路。目标3中的研究将：（i）定义在缺失PITX1后在关节软骨中受到干扰的关键靶基因和下游信号传导途径，和（ii）提供骨关节炎疾病模型，其中确定靶向PITX1信号传导的易处理性和治疗潜力。这些研究将为骨关节炎的细胞和分子基础提供新的和详细的理解，并确定预防和治疗骨关节炎的新药物靶点。这是一种常见的、令人衰弱的、却被忽视的疾病。

项目成果

Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.

• DOI: 10.1172/jci.insight.168796
• 发表时间: 2023-06-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Loisay, Lea;Komla-Ebri, Davide;Morice, Anne;Heuze, Yann;Viaut, Camille;Seigliere, Amelie de La;Kaci, Nabil;Chan, Danny;Lamouroux, Audrey;Baujat, Genevieve;Bassett, J. H. Duncan;Williams, Graham R.;Legeai-Mallet, Laurence
• 通讯作者: Legeai-Mallet, Laurence

Year in Thyroidology: Basic Science

甲状腺学年：基础科学

• DOI: 10.1089/thy.2023.0520
• 发表时间: 2024
• 期刊: Thyroid®
• 作者: Williams G