Cellular and Molecular Pathogenesis of Osteoarthritis

研究背景骨关节炎是导致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%，现在影响到全世界5亿多人。15%的英国人患有骨关节炎，每年造成148亿英镑的经济损失。尽管造成了巨大的个人、经济和社会损失，骨关节炎仍然是一种普遍被忽视的疾病，最近成立了《柳叶刀》委员会来直接解决这一问题。骨关节炎会导致软骨的逐渐磨损和撕裂以及正常组织修复的失败，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。对人类的研究由于纳入了不同年龄、性别、种族和病因的患者而变得复杂。它们也缺乏与正常关节的关键比较信息，因为只有在终末期疾病的关节置换术中获得的组织才能被研究。因此，人体研究无法建立基因表达变化与疾病机制之间的因果关系。因此，治疗骨关节炎的唯一方法是关节置换术，而且没有药物可以预防疾病的发生或进展。现在需要一种新的、公正的方法，使用一种完善和有效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需求。目的和目的我们假设在疾病发生和进展期间从小鼠膝关节获得的组织特异性基因表达模式（空间转录组学）将确定骨关节炎的关键靶细胞、基因、主要途径和信号网络。目的1。对正常、老年和骨关节炎小鼠的膝关节进行详细的成像和组织特异性空间转录组学研究。目标2。优先考虑骨关节炎发病和进展的关键基因和信号通路。我们最近在缺乏Pitx1基因两个拷贝之一的小鼠中发现了严重的早发性骨关节炎。因此，在Aim 3中，我们将确定PITX1在骨关节炎中的作用，并确定其在软骨中的作用机制。目标3。确定Pitx1在体内骨关节炎的发生和发展中的作用。应用和益处Aim 1的研究将：(i)确定膝关节的细胞和分子图谱，（ii）确定疾病发生和进展期间细胞和分子程序的顺序变化。Aim 2的研究将：(i)整合多种互补的小鼠和人类数据集；（ii）优先考虑和验证参与骨关节炎发病和进展的关键和可处理的保守基因和主要信号通路。Aim 3中的研究将：(i)定义Pitx1缺失后关节软骨中受到干扰的关键靶基因和下游信号通路；（ii）提供骨关节炎疾病模型，以确定靶向Pitx1信号的可追踪性和治疗潜力。总的来说，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，并为预防和治疗这种常见的、使人衰弱的、但被忽视的疾病确定新的药物靶点。

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.