Unravelling of pathomechanisms for plastin 3 associated bone and cartilage diseases

纤溶酶原激活素3(PLS3)是一种普遍表达的肌动蛋白结合和捆绑蛋白，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)相连。这使得对组织形态发生、分化和动态平衡至关重要的化学和机械信号的传输成为可能。PLS3的变异会导致男性骨质疏松和骨折。我们最近发现，在小鼠中，PLS3基因敲除会导致骨质疏松，而PLS3过表达则会导致骨质增生。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、内小体形态和V-ATPase定位的改变。此外，我们的研究表明，根据PLS3水平的不同，膝关节会发生变化，这与骨关节炎的软骨退化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PLS3的缺乏或过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中断，从而导致骨和软骨细胞外基质相关疾病的原因。破译这些基本机制可能有助于开发新的药物疗法和疗法。

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.