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

骨骼和免疫系统的特点是紧密相连的细胞，这些细胞通过许多分子直接和/或间接通信，其中许多分子是共享的。分子网络包括细胞因子和黏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和骨细胞中都是活跃的。然而，这些通信网络是如何运作的，以及所涉及的分子的性质还远未被了解。我们确定SWAP-70是一种对免疫细胞和破骨细胞都很重要的蛋白质，这为我们提供了一个解开这种关系的模型。初步数据显示，SWAP-70基因缺陷小鼠具有严重的退骨作用，产生的破骨细胞吸收受损，核数量减少，在造血干细胞发育和特定造血系的分化方面表现出特定的缺陷。SWAP-70在B细胞中表达，但最近的证据表明，在某些前体细胞HSCs中也有表达，在激活的T细胞和Treg中也有表达，已知这些细胞影响骨形成和骨吸收。在这里，我们建议(1)确定SWAP-70-/-小鼠的骨化病对造血干细胞生态位的影响：(2)确定SWAP-70-/-破骨细胞前体细胞的体外和体内分化以及SWAP-70依赖的淋巴系向髓系的转换；(3)了解免疫系统细胞--尤其是T和B细胞--在SWAP-70-小鼠体内对骨形成的影响。这些研究不仅将加深我们对控制造血细胞和骨生物学的重要因子SWAP-70的理解，而且还将有助于我们对骨-免疫系统相互作用的总体认识。

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.