Unravelling of pathomechanisms for plastin 3 associated bone and cartilage diseases

揭示plastin 3相关骨和软骨疾病的病理机制

• 批准号: 407176282
• 负责人: Professorin Dr. Anja Niehoff
• 金额: --
• 依托单位: Institut für Humangenetik
• 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/407176282?language=en
• 关键词: Unravelling; pathomechanisms; plastin; associated; bone

Plastin 3 (PLS3) is a ubiquitously expressed actin-binding and -bundling protein that regulates the dynamics of the actin cytoskeleton. The actin cytoskeleton is connected to the extracellular matrix (ECM) via cell surface integrins. This enables the transmission of crucial chemical and mechanical signals for tissue morphogenesis, differentiation and homeostasis. Variants in PLS3 cause osteoporosis with fractures in men. We recently found that Pls3 knock-out in mice leads to osteoporosis whereas PLS3 overexpression results in hyperostosis. Very recently, we have shown that endocytosis is disturbed in osteoclasts, which leads to changes in vesicle trafficking, the morphology of endosomes and the localization of V-ATPase. In addition, our investigations indicated that, depending on the PLS3 level, alterations in the knee joint occur, which are associated with cartilage degeneration in osteoarthritis and a change in the phenotype of chondrocyte. In this project, we aim to understand how a deficiency or an overexpression of PLS3 leads to a disruption of basic cellular processes that are dependent on the dynamics of the actin cytoskeleton, and thus, are the cause of bone and cartilage ECM-associated diseases. Deciphering these basic mechanisms could help develop new drug treatments and therapies.

Plastin 3（PLS 3）是一种广泛表达的肌动蛋白结合和捆绑蛋白，其调节肌动蛋白细胞骨架的动力学。肌动蛋白细胞骨架通过细胞表面整合素与细胞外基质（ECM）连接。这使得关键的化学和机械信号的组织形态发生，分化和稳态的传输。PLS 3的变体导致男性骨质疏松症和骨折。我们最近发现小鼠中Pls 3基因敲除会导致骨质疏松症，而Pls 3过表达会导致骨质增生。最近，我们发现破骨细胞的内吞作用受到干扰，导致囊泡运输、内体形态和V-ATP酶定位的变化。此外，我们的研究表明，根据PLS 3水平，膝关节发生变化，这与骨关节炎中的软骨变性和软骨细胞表型的变化有关。在这个项目中，我们的目标是了解PLS 3的缺乏或过度表达如何导致依赖于肌动蛋白细胞骨架动力学的基本细胞过程的破坏，从而导致骨和软骨ECM相关疾病。破译这些基本机制可以帮助开发新的药物治疗和疗法。