University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
PLoS One. 2010 Oct 27;5(10):e13657. doi: 10.1371/journal.pone.0013657.
Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control. Flt-3L alone increased adherent and non-adherent cells. PTH did not directly impact hematopoietic or osteoclastic cells but acted in concert with Flt-3L to further increase cell numbers. Flt-3L alone stimulated proliferation, while PTH combined with Flt-3L decreased apoptosis. Flt-3L increased blasts early in culture, and later increased CD45(+) and CD11b(+) cells. In parallel experiments, IL-6 acted additively with Flt-3L to increase cell numbers and IL-6-deficient bone marrow cultures (compared to wildtype controls) but failed to amplify in response to Flt-3L and PTH, suggesting that IL-6 mediated the PTH effect. In vivo, PTH increased Lin(-) Sca-1(+)c-Kit(+) (LSK) hematopoietic progenitor cells after PTH treatment in wildtype mice, but failed to increase LSKs in IL-6-deficient mice. In conclusion, PTH acts with Flt-3L to maintain hematopoietic cells by limiting apoptosis. IL-6 is a critical mediator of bone marrow cell expansion and is responsible for PTH actions in hematopoietic cell expansion.
甲状旁腺激素 (PTH) 通过作用机制刺激造血细胞，但这些机制仍不明确。白细胞介素-6 (IL-6) 受 PTH 上调并刺激造血。本研究的目的是确定 PTH 和 IL-6 在造血细胞扩增中的作用。从小鼠骨髓中分离出 C57B6 骨髓细胞，用 fms 样酪氨酸激酶-3 配体 (Flt-3L)、PTH、Flt-3L 加 PTH 或载体对照处理。Flt-3L 单独使用即可增加贴壁和非贴壁细胞。PTH 本身并不直接影响造血或破骨细胞，但与 Flt-3L 协同作用以进一步增加细胞数量。Flt-3L 单独刺激细胞增殖，而 PTH 与 Flt-3L 联合使用则减少细胞凋亡。Flt-3L 早期培养时增加母细胞，随后增加 CD45(+) 和 CD11b(+) 细胞。在平行实验中，IL-6 与 Flt-3L 一起增加细胞数量，而缺乏 IL-6 的骨髓培养物（与野生型对照相比）未能对 Flt-3L 和 PTH 产生反应，表明 IL-6 介导了 PTH 的作用。在体内，PTH 在野生型小鼠中治疗后增加了 Lin(-) Sca-1(+)c-Kit(+) (LSK) 造血祖细胞，但未能增加缺乏 IL-6 的小鼠中的 LSK。总之，PTH 通过限制细胞凋亡与 Flt-3L 一起作用以维持造血细胞。IL-6 是骨髓细胞扩增的关键介质，也是 PTH 作用于造血细胞扩增的原因。
