Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, Lyon, France.
PLoS One. 2013 Jun 11;8(6):e65297. doi: 10.1371/journal.pone.0065297. Print 2013.
ITAM-bearing transmembrane signaling adaptors such as DAP12 and FcRγ are important players in bone homeostasis, but their precise role and functions are still unknown. It has been shown that osteoclast differentiation results from the integration of the RANK and of the DAP12 and FcRγ signaling pathways. DAP12-deficient mice suffer from a mild osteopetrosis and culture of their bone marrow cells in the presence of M-CSF and RANKL, fails to give rise to multinucleated osteoclasts. Here, we report that mice overexpressing human DAP12 have an osteopenic bone phenotype due to an increased number of osteoclasts on the surface of trabecular and cortical bone. This enhanced number of osteoclasts is associated with an increased number of proliferating myeloid progenitors in Tg-hDAP12 mice. It is concomitant with an arrest of B cell development at the Pre-Pro B/Pre B stage in the bone marrow of Tg-hDAP12 mice and important decrease of follicular and marginal B cells in the spleen of these animals. Our data show that the overexpression of DAP12 results in both increased osteoclastogenesis and impaired hematopoiesis underlining the relationship between bone homeostasis and hematopoiesis.
携带 ITAM 的跨膜信号转导适配器，如 DAP12 和 FcRγ，是骨稳态中的重要参与者，但它们的确切作用和功能仍不清楚。已经表明，破骨细胞的分化是由 RANK 和 DAP12 和 FcRγ 信号通路的整合引起的。DAP12 缺陷小鼠患有轻度骨质增生症，并且在 M-CSF 和 RANKL 的存在下培养其骨髓细胞，不能产生多核破骨细胞。在这里，我们报告说，过表达人 DAP12 的小鼠由于小梁骨和皮质骨表面破骨细胞数量增加而表现出骨质疏松的骨骼表型。这种破骨细胞数量的增加与 Tg-hDAP12 小鼠中增殖性髓样祖细胞数量的增加有关。这与 Tg-hDAP12 小鼠骨髓中 B 细胞发育在 Pre-Pro B/Pre B 阶段的停滞以及这些动物脾脏中滤泡性和边缘 B 细胞的重要减少同时发生。我们的数据表明，DAP12 的过表达导致破骨细胞生成增加和造血功能受损，强调了骨稳态和造血之间的关系。
