Plastin 3: Unravelling a novel pathomechanism for osteoporosis

• Applicant: Professorin Dr. Brunhilde Wirth
• Subject Area: Human Genetics
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 263785055

Osteoporosis represents one of the ten most frequently occurring diseases in elderly people, particularly affecting women after menopause. Osteoporosis causes fractures especially in the upper limbs, femoral neck and vertebral bodies. Early osteoporosis with fractures and osteogenesis imperfecta (OI) are monogenic inherited diseases with a high variability in age of onset and severity, caused by mutations in various genes involved in cartilage formation and assembly, bone generation or resorption. In a productive collaborative work with the groups of Gerard Pals (Amsterdam) and Carola Zillikens (Rotterdam), we succeeded in identifying familial pathogenic variants in the X-linked Plastin 3 gene (PLS3) in men with early osteoporosis with fractures and women with mild osteoporosis. Furthermore, in a large Rotterdam cohort the most significant association with a SNP in PLS3 was identified, which correlates with low bone mineral density and osteoporosis in women. PLS3 is a Ca2+-dependent F-actin bundling protein with an essential role in cell migration, endocytosis und all F-actin-dependent cellular processes. We have shown that morpholino-mediated pls3 knockdown in zebrafish causes dramatic deformities in craniofacial skeletal and muscle structures. These were fully rescued by co-injection of PLS3 RNA (van Dijk et al. N Engl J Med 2013). In another project we showed that in women overexpression of PLS3 is a protective modifier for spinal muscular atrophy (SMA), a frequently occurring neuromuscular disease (Oprea et al. Science 2008). To unravel the protective mechanism, we generated a conditional PLS3 overexpressing mouse and we showed that all F-actin bundling processes at the neuromuscular junction level are restored (Ackermann et al Hum Mol Genet 2013). Preliminary data generated in this project showed that mice overexpressing PLS3 have thicker cortical and trabecular bone structures. PLS3 overexpression can be found in about 5% of the general population and might correlate with protection against osteoporosis or OI. In the context of this application, we aim at unravelling the pathomechanism underlying PLS3 depletion by using conditional knock-out mice. We will generate mice lacking Pls3 either ubiquitously or cell-type -specifically by depleting Pls3 in osteoblasts/osteocytes or in skeletal muscle. A full battery of morphological, histological, cellular, molecular and biochemical in vitro and ex vivo experiments will be carried out to determine the underlying pathomechanism of osteoporosis caused by loss of PLS3. We identified 10 novel PLS3-interacting partners, which represent valuable resources to unravel the molecular mechanism. Understanding the molecular pathomechanism of osteoporosis will open new avenues for future therapies.

• DFG Programme: Research Grants
• Participating Person: Professorin Dr. Anja Niehoff