Repurposing Alpha-1-antitrypsin as a treatment for post-traumatic osteoarthritis

骨关节炎(OA)是最常见的关节疾病，在全球数亿人中导致慢性疼痛和残疾。我们的关节之所以起作用，是因为有一种特殊的组织层，称为软骨，它保持骨骼边缘的光滑，避免磨损。如果软骨被创伤事件破坏，或者被老化和微创侵蚀，就会出现以关节功能障碍(缺乏灵活性)和极度疼痛为特征的疾病。在这里，我们关注的是创伤引起的韧带或软骨损伤，它们占全球骨性关节炎总负担的12%以上：即使使用最好的治疗方法，这些患者中也有相当大一部分(约40%)会患上骨关节炎。手术稳定关节是治疗创伤引起的韧带或软骨损伤的方法；然而，研究表明，手术稳定后持续的炎症在推动骨性关节炎的进展中起着至关重要的作用。因此，我们建议对关节损伤后减轻炎症和促进软骨修复的因素进行早期干预，可以防止进一步的损伤和创伤后骨关节炎的发展。我们已经确定了一个这样的因子，并将其命名为α1-抗胰蛋白酶(AAT)。有了这个建议，我们寻求资金来研究AAT在实验性创伤后骨关节炎中的基础生物学；了解它的工作原理可以为更好地管理骨关节炎开辟创新的治疗方法。这一假设将通过三个实验对象进行检验。利用人类软骨细胞研究AAT的分子机制，软骨细胞是产生软骨的细胞。我们的目标是揭示AAT如何刺激软骨生长以修复创伤后的缺陷。这包括研究AAT与细胞表面的对应物(通常称为受体)的相互作用，以及研究相互作用发生后细胞内发生的事情。评估AAT在治疗软骨损伤修复中的潜力。我们将使用一种被批准的名为Prolastin-C的AAT产品进行实验，以评估其在再生受损软骨和骨缺损方面的效果。我们的研究将涉及创伤后骨关节炎的实验室测试和临床前模型。探讨内源性AAT在软骨再生中的作用。在这里，我们将使用缺乏产生AAT的基因的转基因小鼠。这些动物在商业上是可用的，而且是可行的。我们将把它们应用于我们的关节损伤模型，以评估在关节损伤的情况下，自然产生的AAT是否以及如何有助于软骨的维护和修复。该项目完成后，可能会将AAT确定为一种新的治疗疾病的骨关节炎药物。由于Prolastin-C(由Grifols生产的血浆AAT)已经用于治疗AAT罕见遗传缺陷患者的肺部疾病，我们认为该项目可以指导这种新治疗剂的快速再利用试验。综上所述，我们的目标是揭示AAT影响软骨细胞和促进骨关节炎患者细胞和动物软骨修复的机制。在项目完成后，在进一步的资金支持下，我们的最终目标是开发基于AAT的药物，可以减缓骨关节炎的进展，并为患有这种疾病的个人提供长期缓解。

Osteoarthritis (OA) is the most common joint disease that causes chronic pain and disability in hundreds of millions of people globally. Our joints work because there is a special tissue layer, called cartilage, which maintains the edge of the bones smooth and avoids attrition. If cartilage is broken down by traumatic events or eroded by ageing and also micro-traumas, there is disease characterized by joint malfunctioning (lack of mobility) and excruciating pain. Here we focus on trauma-induced ligament or cartilage injuries which contributes to over 12% of the overall OA burden worldwide: a significant proportion of these patients (~40%) develop osteoarthritis even with the best available treatments. Surgical stabilisation of the joint is the treatment for trauma-induced ligament or cartilage injuries; however, research indicates that ongoing inflammation following surgical stabilization plays a crucial role in driving progression to osteoarthritis. Therefore, we propose that early intervention with factors that mitigate inflammation and promote cartilage repair after joint injury can prevent further damage and the development of post-traumatic osteoarthritis. We have identified one such factors, and it is termed alpha1-antitrypsin (AAT).With this proposal we seek funding to study the fundamental biology of AAT in experimental post-traumatic osteoarthritis; understanding how it works can open innovative therapeutic approaches for better management of osteoarthritis. This hypothesis will be tested by three experimental objectives.1. Study the molecular mechanisms of AAT using human chondrocytes, the cells that produce the cartilage. We aim to unravel how AAT stimulates cartilage growth to repair post-traumatic defects. This involves investigating AAT interaction with counterparts on the cell surface (often called receptors) and study what happens within the cell after the interaction takes place.2. Evaluate the potential of AAT for therapeutic repair of cartilage damage. We will conduct experiments using an approved AAT product called Prolastin-C to assess its efficacy in regenerating damaged cartilage and bone defects. Our research will involve laboratory tests as well as pre-clinical models of post-traumatic osteoarthritis.3. Investigate the role of endogenous AAT on cartilage regeneration. Here we will use mice genetically modified to lack the genes that produce AAT. These animals are commercially available and viable. We will apply them to our model of joint injury, to assess if and how naturally occurring AAT contributes to cartilage maintenance and repair in the context of joint injuries.At completion this project may identify AAT as a novel disease-modifying osteoarthritic drug. Since Prolastin-C (plasma AAT, produced by Grifols) is already used to treat lung disease in individuals with the rare genetic deficiency in AAT, we reason that this project can guide a rapid repurposing trial for this new therapeutic agent. In summary, we aim to uncover the mechanisms by which AAT influences chondrocytes and promotes cartilage repair with human cells and animals with osteoarthritis. At project completion, and with further funding support, our ultimate objective is to develop AAT-based drugs that can slow down the progression of osteoarthritis and provide long-term relief for individuals suffering from the condition.