Interplay between the Immune System and the Bone in the SWAP-70-/-mouse

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The bone and the immune system feature intimately interconnected cells, which communicate directly and/or indirectly through a number of molecules, of which many are shared. The molecular networks include the cytokine and adhesion systems with their ligands and receptors. In addition, many intracellular signaling molecules and transcription factors are active in immune and bone cells. However, how these communication networks function and the nature of molecules that are involved is far from understood. Our identification of SWAP-70 as a protein important for both, immune cells and osteoclasts provides a model to unravel such relationships. Preliminary data show that SWAP-70 deficient mice are severely osteopetrotic, generate resorption-impaired osteoclasts with reduced number of nuclei, and show specific deficiencies in hematopoietic stem cell development and differentiation of specific hematopoietic lineages. SWAP-70 is expressed in B cells, but as recent evidence shows also in HSCs, certain precursors, and in activated T cells and Treg, known to affect bone formation and resorption. Here, we propose (1) to define the impact of osteopetrosis in SWAP-70-/- mice on the hematopoietic stem cell niche; (2) to determine in vitro and in vivo differentiation of SWAP-70-/- osteoclast precursors and the SWAP-70-dependent lymphoid-to-myeloid lineage switch; (3) to understand the impact of cells of the immune system – in particular T and B cells – on bone formation in SWAP-70-/- mice.These studies will not only enhance our understanding of an important factor, SWAP-70, which controls hematopoietic cells and as is now apparent also osteobiology, but will also contribute to our general insights into the bone-immune system interplay.