Cellular and Molecular Pathogenesis of Osteoarthritis

骨性关节炎是导致疼痛和残疾的主要原因。在过去的30年里，它的发病率增加了50%，现在全世界有超过5亿人受到影响。英国15%的人口患有骨性关节炎，每年的经济损失为148亿GB。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，最近成立了一个柳叶刀委员会来直接解决这个问题。骨关节炎会导致软骨的进行性磨损和正常组织修复的失败，最终导致关节破坏。由于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，因此了解骨关节炎是如何开始和发展的是有限的。在人类身上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。他们也缺乏来自正常关节的关键比较信息，因为只有在关节置换治疗终末期疾病时获得的组织才能被研究。因此，人类研究无法确定基因表达变化与疾病机制之间的因果关系。因此，骨关节炎的唯一治疗方法是关节置换，目前还没有可以防止疾病发生或发展的药物。现在需要一种新的和公正的方法，使用建立和验证的骨关节炎疾病模型来推动该领域的发展，并解决这一关键的未得到满足的需求。AIMS和目标我们假设，在疾病的发生和发展过程中从小鼠膝关节获得的组织特定的基因表达模式(空间转录)将识别定义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。目的2.确定支持骨关节炎发生和发展的关键基因和信号通路。我们最近发现，在两个拷贝之一的Pitx1基因缺失的小鼠中，存在严重的早发性骨关节炎。因此，在目标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。目的3.确定PITX1在活体骨关节炎发生和发展中的作用。应用和BENEFITS目标1中的研究将：(I)定义膝关节的细胞和分子图谱，(Ii)确定疾病发生和发展过程中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，以及(Ii)优先处理和验证关键和易处理的保守基因和涉及骨关节炎发生和发展的主要信号通路。目标3的研究将：(I)确定Pitx1缺失后关节软骨中受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信号的可控性和治疗潜力。总之，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、衰弱的、但被忽视的疾病寻找新的药物靶点。

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.