Mitochondrial dysfunction in cartilage and its consequences for extracellular matrix and joint homeostasis

软骨线粒体功能障碍及其对细胞外基质和关节稳态的影响

• 批准号: 407146744
• 负责人: Professor Dr. Bent Brachvogel
• 金额: --
• 依托单位: Klinik und Poliklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/407146744?language=en
• 关键词: Mitochondrial; dysfunction; cartilage; its; consequences

The extracellular matrix (ECM) of the cartilage is mainly composed of the collagen-based fibrillar network and the proteoglycan-enriched extrafibrillar matrix and its stability is conferred by the functional interaction of the two compartments. Changes in the interaction or destabilization of the ECM compartments profoundly impair cartilage and bone homeostasis leading to chondrodysplasias or degenerative skeletal diseases. Very recently, we showed that mitochondrial respiration chain (mtRC) function is a crucial metabolic cue for skeletal growth and ECM formation in cartilage. We have now collected evidence that metabolic signalling pathways are activated in chondrocytes with mtRC dysfunction and are associated with the disturbed vesicle trafficking that impair ECM secretion and subsequent assembly and crosslinking in cartilage. In this project, we aim to understand through which metabolic signalling mechanisms is mtRC dysfunction translated into disturbed vesicle-mediated ECM secretion and assembly processes in cartilage. Our studies will reveal not only how chronic mtRC dysfunction disturbs cell survival and ECM homeostasis in skeletal tissues, but could also open new channels of drug discovery. Thus, we may reveal additional therapeutic options to treat ECM damage in mitochondrial diseases and in progressive cartilage degeneration that are associated with mtRC dysfunction.

软骨的细胞外基质（ECM）主要由基于胶原蛋白的原纤维网络和富含蛋白聚糖的外部纤维矩阵组成，其稳定性由两个隔室的功能相互作用赋予。 ECM隔室的相互作用或不稳定的变化会严重损害软骨和骨稳态，导致软骨发育不全或退化性骨骼疾病。最近，我们表明线粒体呼吸链（MTRC）功能是软骨中骨骼生长和ECM形成的至关重要的代谢提示。现在，我们收集了证据表明，代谢信号通路在具有MTRC功能障碍的软骨细胞中被激活，并且与受干扰的囊泡运输有关，这些囊泡运输会损害ECM的分泌以及随后的装配和在软骨中的交叉链接。在这个项目中，我们旨在了解哪些代谢信号传导机制是MTRC功能障碍，转化为囊泡介导的ECM分泌和软骨中的组装过程。我们的研究不仅会揭示慢性MTRC功能障碍在骨骼组织中如何打扰细胞存活和ECM稳态，而且还可以打开新的药物发现通道。因此，我们可能会揭示其他治疗方法，以治疗与MTRC功能障碍相关的线粒体疾病中的ECM损伤和进行性软骨变性。