Division of Immunology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12385-90. doi: 10.1073/pnas.1216082110. Epub 2013 Jul 5.
Osteoclasts (OCs) are bone-resorbing cells that are formed from hematopoietic precursors. OCs ordinarily maintain bone homeostasis, but they can also cause major pathology in autoimmune and inflammatory diseases. Under homeostatic conditions, receptor activator of nuclear factor kappa-B (RANK) ligand on osteoblasts drives OC differentiation by interaction with its receptor RANK on OC precursors. During chronic immune activation, RANK ligand on activated immune cells likewise drives pathogenic OC differentiation. We here report that the related TNF family member CD70 and its receptor CD27 can also mediate cross-talk between immune cells and OC precursors. We identified CD27 on a rare population (0.3%) of B220(-)c-Kit(+)CD115(+)CD11b(low) cells in the mouse bone marrow (BM) that are highly enriched for osteoclastogenic potential. We dissected this population into CD27(high) common precursors of OC, dendritic cells (DCs) and macrophages and CD27(low/neg) downstream precursors that could differentiate into OC and macrophages, but not DC. In a recombinant mouse model of chronic immune activation, sustained CD27/CD70 interactions caused an accumulation of OC precursors and a reduction in OC activity. These events were due to a CD27/CD70-dependent inhibition of OC differentiation from the OC precursors by BM-infiltrating, CD70(+)-activated immune cells. DC numbers in BM and spleen were increased, suggesting a skewing of the OC precursors toward DC differentiation. The impediment in OC differentiation culminated in a high trabecular bone mass pathology. Mice additionally presented anemia, leukopenia, and splenomegaly. Thus, under conditions of constitutive CD70 expression reflecting chronic immune activation, the CD27/CD70 system inhibits OC differentiation and favors DC differentiation.
破骨细胞 (OC) 是一种骨吸收细胞，由造血前体细胞形成。OC 通常维持骨稳态，但在自身免疫和炎症性疾病中也会引起主要的病理学变化。在稳态条件下，成骨细胞表面的核因子 κB 受体激活剂 (RANK) 配体通过与 OC 前体细胞表面的受体 RANK 相互作用来驱动 OC 分化。在慢性免疫激活期间，激活的免疫细胞表面的 RANK 配体也驱动致病性 OC 分化。我们在此报告，相关的 TNF 家族成员 CD70 及其受体 CD27 也可以介导免疫细胞和 OC 前体细胞之间的交叉对话。我们在小鼠骨髓 (BM) 中鉴定出 B220(-)c-Kit(+)CD115(+)CD11b(low)细胞的一个罕见群体 (0.3%) 上表达 CD27，该细胞群中富含 OC 生成潜能。我们将该群体分为 CD27(high)OC 的共同前体细胞、树突状细胞 (DC) 和巨噬细胞以及 CD27(low/neg)下游前体细胞，它们可以分化为 OC 和巨噬细胞，但不能分化为 DC。在慢性免疫激活的重组小鼠模型中，持续的 CD27/CD70 相互作用导致 OC 前体的积累和 OC 活性的降低。这些事件是由于 BM 浸润的 CD70(+)激活免疫细胞通过 CD27/CD70 依赖性抑制 OC 前体向 OC 的分化而引起的。BM 和脾脏中的 DC 数量增加，表明 OC 前体向 DC 分化的偏向。OC 分化的受阻最终导致小梁骨量增加的病理变化。小鼠还表现出贫血、白细胞减少和脾肿大。因此，在持续表达 CD70 反映慢性免疫激活的情况下，CD27/CD70 系统抑制 OC 分化并有利于 DC 分化。
