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

骨骼和免疫系统的特征是紧密相连的细胞，它们通过许多分子直接和/或间接地进行通信，其中许多分子是共享的。分子网络包括细胞因子和粘附系统及其配体和受体。此外，许多细胞内信号分子和转录因子在免疫细胞和骨细胞中是活跃的。然而，这些通信网络如何运作以及所涉及的分子的性质还远未被理解。我们将SWAP-70鉴定为对免疫细胞和破骨细胞都很重要的蛋白质，为解开这种关系提供了一个模型。初步数据显示，SWAP-70缺陷型小鼠是严重的骨硬化，产生细胞核数量减少的吸收受损的破骨细胞，并显示出特定的造血干细胞发育和特定造血谱系分化的特定缺陷。SWAP-70在B细胞中表达，但最近的证据表明，它也在HSC、某些前体细胞和活化的T细胞和Treg中表达，已知它们影响骨形成和再吸收。在此，我们提出：（1）确定SWAP-70-/-小鼠中骨石化病对造血干细胞生态位的影响;（2）确定SWAP-70-/-破骨细胞前体的体外和体内分化以及SWAP-70依赖的淋巴细胞向骨髓细胞谱系转换;（3）了解免疫系统的细胞--特别是T和B细胞--对SWAP-70-/-小鼠骨形成的影响。这些研究不仅将增强我们对一个重要因素的理解，SWAP-70，它控制造血细胞，现在很明显也是骨生物学，但也将有助于我们对骨免疫系统相互作用的一般见解。

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.