Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
PLoS One. 2010 May 27;5(5):e10853. doi: 10.1371/journal.pone.0010853.
It is well established that bleeding activates the hematopoietic system to regenerate the loss of mature blood elements. We have shown that hematopoietic stem cells (HSCs) isolated from animals challenged with an acute bleed regulate osteoblast differentiation from marrow stromal cells. This suggests that HSCs participate in bone formation where the molecular basis for this activity is the production of BMP2 and BMP6 by HSCs. Yet, what stimulates HSCs to produce BMPs is unclear.
METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate that erythropoietin (Epo) activates Jak-Stat signaling pathways in HSCs which leads to the production of BMPs. Critically, Epo also directly activates mesenchymal cells to form osteoblasts in vitro, which in vivo leads to bone formation. Importantly, Epo first activates osteoclastogenesis which is later followed by osteoblastogenesis that is induced by either Epo directly or the expression of BMPs by HSCs to form bone.
CONCLUSIONS/SIGNIFICANCE: These data for the first time demonstrate that Epo regulates the formation of bone by both direct and indirect pathways, and further demonstrates the exquisite coupling between hematopoiesis and osteopoiesis in the marrow.
众所周知，出血会激活造血系统，从而再生成熟血液成分的损失。我们已经表明，从受到急性出血挑战的动物中分离出的造血干细胞（HSCs）调节骨髓基质细胞向成骨细胞的分化。这表明 HSCs 参与骨形成，其活性的分子基础是 HSCs 产生 BMP2 和 BMP6。然而，是什么刺激 HSCs 产生 BMPs 尚不清楚。
方法/主要发现：在这项研究中，我们证明了促红细胞生成素（Epo）激活 HSCs 中的 Jak-Stat 信号通路，从而导致 BMP 的产生。关键的是，Epo 还可以直接激活间充质细胞，在体外形成成骨细胞，而在体内则导致骨形成。重要的是，Epo 首先激活破骨细胞生成，随后被 HSCs 直接表达或由 HSCs 表达的 BMPs 诱导的成骨细胞生成诱导骨形成。
结论/意义：这些数据首次表明，Epo 通过直接和间接途径调节骨的形成，并进一步表明骨髓中造血和骨形成之间的精细耦合。
