Harnessing temporomandibular disc development to enhance regeneration

颞下颌关节（TMJ）是人体最常用的关节之一。它形成于下颌骨和颅底之间。圆盘位于这些元素之间。这个椎间盘是由一种叫做纤维软骨的组织构成的，起到缓冲的作用。颞下颌关节紊乱（TMDs）是指下颌关节的结构、功能或生理紊乱。症状包括慢性关节疼痛、关节不舒服的砰砰声或咔嚓声、头痛、颌锁和张嘴困难。tmd非常普遍，影响了多达20%的人口。因此，tmd对患者的生活产生负面影响，并通过管理费用、获得医疗和牙科服务的机会增加以及失去就业日数而产生更广泛的社会和经济影响。高达70%的TMDs是由TMJ椎间盘移位引起的，这可能导致椎间盘穿孔。反过来，椎间盘移位和损伤与破坏性关节骨关节炎有关。这些最严重的TMD病例的手术治疗选择包括切除受损的椎间盘（椎间盘切除术）或关节重建，使用患者组织（通常来自肋骨）或合成材料。这些策略都不能令人满意。椎间盘切除术可导致关节退行性改变，而重建通常会导致最终的关节融合。因此，椎间盘修复是一个重要的研究领域，以创造新的和改进的治疗方法。为了修复椎间盘，有两种可能的策略。提供新的椎间盘细胞来源，或促进现有的椎间盘细胞增殖和修复损伤。为了实现第一种方法，能够创建椎间盘细胞是很重要的。为此，我们可以了解盘状细胞在胚胎中是如何形成的。然后可以模仿这个过程来创建新的光盘细胞来源。除了来自周围组织的分子信号外，形成的盘细胞还受到机械力的影响，这决定了它们的形成方式。因此，我们也将研究这些力是如何塑造圆盘的。我们将使用老鼠胚胎进行这项研究，老鼠胚胎的椎间盘与人类胚胎非常相似，并允许我们使用最新的老鼠遗传学技术来跟踪细胞的命运。对于第二种方法，我们将研究成年小鼠椎间盘中是否存在常驻干细胞群。我们将观察是否可以通过改变它们的信号环境或机械环境，或两者兼而有之，刺激椎间盘细胞来修复损伤。这是可能的，因为我们可以在培养皿中培养老鼠圆盘，施加力或改变信号因素，观察对圆盘细胞的影响。我们提出的实验将提供重要的见解，了解圆盘是如何形成的，它是由什么细胞形成的，以及产生这种独特细胞群的重要机械和分子线索。我们还将提供成人椎间盘细胞的新信息和刺激修复受损椎间盘的选择。通过我们的研究结果，我们的目标是提供知识，以允许更有效，侵入性更小，生物学驱动的方法来处理TMJ缺陷。

The temporomandibular jaw joint (TMJ) is one of the most used joints in the body. It is formed between the mandible bone in the lower jaw and the base of the skull. A disc sits between these elements. This disc is made of a tissue called fibrocartilage and acts as a cushion. Temporomandibular joint disorders (TMDs) are disruptions in the structure, function, or physiology of the jaw joint. Symptoms include chronic joint pain, uncomfortable popping or clicking in the joint, headaches, jaw locking, and difficulty opening the mouth. TMDs are very common, affecting up to 20% of the population. As such TMDs have a negative impact on sufferers' lives, as well as a wider societal and economic impact through management costs, increased access to medical and dental services, and employment days lost. Up to 70% of TMDs are due to TMJ disc displacement, which can lead to perforation of the disc. In turn, disc displacement and damage are associated with destructive osteoarthritis of the joint. Surgical treatment options for these most severe cases of TMD include removal of the damaged disc (discectomy) or joint reconstruction, with either tissue from the patient (typically from the ribs) or synthetic materials. These strategies are both unsatisfactory. Discectomy can lead to degenerative changes to the joint, while reconstruction often results in eventual joint fusion. Therefore, disc repair is an important area for research in order to create new and improved treatments. In order to repair the disc, there are two potential strategies. Providing a new source of disc cells, or encouraging the existing disc cells to proliferate and repair the damage. In order to achieve the first approach, it is important to be able to create disc cells. For this, we can learn from how the disc cells are formed in the first place in the embryo. This process can then be mimicked to create a new source of disc cells. In addition to molecular signals from the surrounding tissues, the forming disc cells are also subject to mechanical force, which shapes how they form. We will therefore also investigate how these forces shape the disc.We will carry out this research using mouse embryos, which have a very similar disc to human embryos, and allow us to follow the fate of cells using the latest techniques in mouse genetics.For the second approach, we will investigate whether there is a resident population of stem cells in the adult mouse disc. We will look at whether the disc cells can be stimulated to repair the damage, either by altering their signalling environment or their mechanical environment or both. This is possible as we can culture mouse discs in a dish and apply force or alter signalling factors and watch the effect on the disc cells.Our proposed experiments will provide important insight into how the disc forms, the cells that it is created from, and the mechanical and molecular cues that are important to create this unique population of cells. We will also provide new information about the cells of the adult disc and the options for stimulating repair to damaged discs. With our results, we aim to provide the knowledge to allow more effective, less invasive, biology-driven methods to deal with TMJ defects.