How Fra/AP-1 transcription factors control the bone niche

Fra/AP-1转录因子如何控制骨生态位

• 批准号: 237586472
• 负责人: Professorin Dr. Aline Bozec, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik 3 - Rheumatologie und Immunologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/237586472?language=en
• 关键词: How; Fra; AP; transcription; factors

Bone is a dynamic tissue regulated by the balance between osteoblasts, the bone forming cells and osteoclasts, the bone resorbing cells. Current concepts are that i) bone degradation is also regulated by the immune system ii) bone formation and inflammation interact and iii) bone and bone marrow form niches for the development and the survival of hematopoietic stem cells (HSC) and immune cells, in particular B-cells. Thus, interactions between bone remodeling and the immune system are necessary for proper bone homeostasis and HSC/immune cell niches. On one hand, we have recently demonstrated that Fra/AP-1 proteins are important transcription factors controlling the fate of osteoblasts. Preliminary data show that Fra-2 expression in osteoblasts induces systemic inflammation with increased macrophage infiltration but reduced B cell numbers in spleen and bone marrow. However, the molecular mechanisms how Fra-2 expression by osteoblasts induces inflammation and dampens B-cell development are not yet defined. On the other hand, Fra-1 is able to regulate B-cell development and humoral immune responses in cellautonomous manner. Preliminary results show that Fra-1 deletion in B-cells leads to a decreased bone volume in mice. The molecular mechanism leading to this bone alteration remains to be analyzed. Based on these two observations, we want to elucidate the crosstalk between the bone niche and immune cells, especially B-cells, regulated by Fra-1 and Fra-2 transcription factors. 1) We will describe the consequence of Fra-1 and Fra-2 deletion in B-cells on bone homeostasis and 2) analyze the effect of Fra-1 and Fra-2 expression in osteoblasts on B-cell development, humoral immune responses and inflammation. Hence, depicting the molecular mechanism underlying the crosstalk between osteoblast and immune cells in the bone marrow will add new insights in the comprehension of the bone marrow niches and bone cell-immune cell interactions.

骨是一种动态的组织，由成骨细胞（骨形成细胞）和破骨细胞（骨吸收细胞）之间的平衡调节。目前的概念是i）骨降解也受免疫系统调节，ii）骨形成和炎症相互作用，iii）骨和骨髓形成造血干细胞（HSC）和免疫细胞（特别是B细胞）发育和存活的小生境。因此，骨重建和免疫系统之间的相互作用对于适当的骨稳态和HSC/免疫细胞小生境是必要的。一方面，我们最近证明Fra/AP-1蛋白是控制成骨细胞命运的重要转录因子。初步数据显示，成骨细胞中的Fra-2表达诱导全身性炎症，其中巨噬细胞浸润增加，但脾和骨髓中的B细胞数量减少。然而，成骨细胞表达Fra-2如何诱导炎症和抑制B细胞发育的分子机制尚未确定。另一方面，Fra-1能够以细胞免疫的方式调节B细胞发育和体液免疫应答。初步结果表明，B细胞中的Fra-1缺失导致小鼠骨体积减少。导致这种骨改变的分子机制仍有待分析。基于这两个观察结果，我们希望阐明骨龛和免疫细胞，特别是B细胞之间的串扰，由Fra-1和Fra-2转录因子调节。1)我们将描述B细胞中Fra-1和Fra-2缺失对骨稳态的影响; 2）分析成骨细胞中Fra-1和Fra-2表达对B细胞发育、体液免疫应答和炎症的影响。因此，描述骨髓中成骨细胞和免疫细胞之间串扰的分子机制将为理解骨髓小生境和骨细胞-免疫细胞相互作用提供新的见解。