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）主要由基于胶原的纤维网络和富含蛋白聚糖的纤维外基质组成，其稳定性是由两个室的功能相互作用赋予的。 ECM 区室相互作用或不稳定的变化会严重损害软骨和骨稳态，导致软骨发育不良或退行性骨骼疾病。最近，我们发现线粒体呼吸链 (mtRC) 功能是骨骼生长和软骨 ECM 形成的关键代谢线索。我们现在收集的证据表明，代谢信号通路在 mtRC 功能障碍的软骨细胞中被激活，并且与囊泡运输紊乱有关，从而损害 ECM 分泌以及随后在软骨中的组装和交联。在这个项目中，我们的目标是了解 mtRC 功能障碍是通过哪种代谢信号机制转化为软骨中囊泡介导的 ECM 分泌和组装过程受到干扰。我们的研究不仅将揭示慢性 mtRC 功能障碍如何扰乱骨骼组织中的细胞存活和 ECM 稳态，而且还可能开辟药物发现的新渠道。因此，我们可能会揭示其他治疗方案来治疗线粒体疾病和与 mtRC 功能障碍相关的进行性软骨退变中的 ECM 损伤。