A novel mouse model for osteopetrosis

• Antragsteller: Professor Dr. Rolf Jessberger
• Fachliche Zuordnung: Zellbiologie
• Förderung: Förderung von 2009 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 122203228

Osteopetrosis is a rare, often inherited bone disease in humans. Brittle bones, stunted growth, bone deformities, and impaired hematopoiesis are characteristic clinical features of affected patients. There is currently no approved therapy, although bone marrow transplantation is being investigated in clinical trials. A decreased number and/or activity of osteoclasts are the cellular hallmarks of osteopetrosis and results in the inability to properly resorb bone. Few mouse models exist for osteopetrosis, and none directly focuses on the F-actin cytoskeletal rearrangements, which are key to osteoclast function. We recently observed a strong osteopetrotic phenotype in the Swap-70-/- mouse. SWAP-70 is a PIP3-binding, RhoGTPaseinteracting, F-actin binding protein expressed in hematopoietic cells. SWAP-70 functions in F-actin rearrangements and controls cell shape, migration, integrinmediated adhesion, homing and related processes. Based on our extensive knowledge of the features of SWAP-70 in the hematopoietic system, we hypothesize that this protein, which we recently found to be expressed in osteoclasts and to localize to F-actin rings, plays a key role in osteoclast biology, specifically in F-actin rearrangement and integrin-mediated adhesion required for osteoclastic bone resorption. Initial experiments showing defective bone resorption by Swap-70-/- monocyte-derived osteoclasts support this hypothesis. We ask for support to investigate this new mouse model for osteopetrosis with the aim to generate fundamentally new insights into bone and osteoclast biology and thus to better understand osteopetrosis, i.e. its origin and its consequences for the bone and hematopoietic systems.

• DFG-Verfahren: Sachbeihilfen
• Beteiligte Person: Dr. Annette Garbe