Zone of Calcified Cartilage – a Natural Boarder in the Osteochondral Unit to Control Diffusion of Molecules between Articular Cartilage and Subchondral Bone

钙化软骨区 â 骨软骨单元中控制分子在关节软骨和软骨下骨之间扩散的天然边界

• 批准号: 491667286
• 负责人: Dr. Andrea Schwab
• 金额: --
• 依托单位: Orthopädische Universitätsklinik
• 依托单位国家: 德国
• 项目类别: WBP Position
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/491667286?language=en
• 关键词: Zone; Calcified; Cartilage; Natural; Boarder

Osteoarthritis (OA) is the commonest joint disease worldwide with more than 20% of the German society suffering from this painful and disabling disease. Physiological and pathological changes during OA include the degeneration and erosion of cartilage tissue up to the exposure of the underlying bone. To intervene the progression of this disease, there is urgent need to better understand the mechanisms at molecular, cell and tissue level of the osteochondral unit, especially the zone of calcified layer (ZCC). The ZCC is connecting the deep zone of non-calcified articular cartilage to the subchondral bone. However, little is known about the role of the ZCC in cartilage homeostasis, the steady state condition of healthy tissue.I hypothesize that the ZCC serves as a natural border that controls the diffusion of molecules between cartilage and bone tissue and regulates cell-cell communication. This permeability is altered upon onset of OA leading to changes in cytokines and morphogens in the extracellular matrix inducing phenotypic changes in chondrocytes. I will approach this topic from two perspectives: the macroscopic tissue-level and the microscopic cellular-level. The first objective covers the quantification of molecules that can pass through human ZCC ex vivo from bone to cartilage and vice versa using advanced 3D imaging techniques and spectrophotometry. The size of molecules passing the ZCC and their location in this thin tissue layer will be correlated to the structural changes in the osteochondral tissue of OA patients. The second objective focuses on the identification of gene expression patterns specific for hypertrophic chondrocytes residing in the calcified cartilage using next generation sequencing technique. This library will be used to compare how specific molecules (morphogens and growth factors) can stimulate chondrocytes isolated from non-calcified cartilage of the deep zone to undergo differentiation towards hypertrophic chondrocytes in vitro and how close these changes match with the phenotype of hypertrophic OA chondrocytes.In close collaboration with the host and guest research groups, I will generate new knowledge and insights on the regulatory role of the ZCC in cartilage homeostasis and OA progression. The characterization of diffusion properties through the ZCC in human explants, together with the response of deep zone chondrocyte to environmental factors in vitro will provide a unique approach to deeper understand the mechanism related to hypertrophic differentiation during OA. This knowledge will result in novel approaches to impede or delay OA progression and cartilage degeneration.

骨关节炎（OA）是世界上最常见的关节疾病，超过20%的德国人患有这种疼痛和致残性疾病。OA期间的生理和病理变化包括软骨组织的退化和侵蚀，直至底层骨的暴露。为了干预这种疾病的进展，迫切需要更好地了解骨软骨单位，特别是钙化层区（ZCC）的分子，细胞和组织水平的机制。ZCC连接非钙化关节软骨的深层与软骨下骨。然而，很少有人知道的ZCC在软骨稳态，健康tissue.I假设，ZCC作为一个自然的边界，控制软骨和骨组织之间的分子扩散和调节细胞-细胞通信的稳态条件的作用。这种渗透性在OA发作时改变，导致细胞外基质中细胞因子和形态发生变化，诱导软骨细胞的表型变化。我将从两个角度来探讨这个话题：宏观组织水平和微观细胞水平。第一个目标涵盖了使用先进的3D成像技术和分光光度法对可以通过人ZCC从骨到软骨的离体分子进行定量，反之亦然。通过ZCC的分子的大小及其在该薄组织层中的位置将与OA患者的骨软骨组织中的结构变化相关。第二个目标是利用下一代测序技术鉴定钙化软骨中肥大软骨细胞的特异性基因表达模式。这个文库将被用来比较特定的分子（形态发生素和生长因子）可以刺激从深层非钙化软骨分离的软骨细胞在体外经历向肥大软骨细胞的分化，以及这些变化与肥大OA软骨细胞表型的匹配程度。在与主持人和嘉宾研究小组的密切合作下，我将对ZCC在软骨稳态和OA进展中的调节作用产生新的知识和见解。通过ZCC在人体外植体中的扩散特性的表征，以及深层软骨细胞对体外环境因素的反应，将提供一种独特的方法来更深入地了解OA过程中肥大分化相关的机制。这些知识将导致新的方法来阻止或延迟OA进展和软骨退变。