Unravelling of pathomechanisms for plastin 3 associated bone and cartilage diseases

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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.