Bethel Monique, Barnes Calvin L T, Taylor Amanda F, Cheng Ying-Hua, Chitteti Brahmananda R, Horowitz Mark C, Bruzzaniti Angela, Srour Edward F, Kacena Melissa A
Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut.
J Cell Physiol. 2015 Sep;230(9):2142-51. doi: 10.1002/jcp.24943.
Emerging data suggest that megakaryocytes (MKs) play a significant role in skeletal homeostasis. Indeed, osteosclerosis observed in several MK-related disorders may be a result of increased numbers of MKs. In support of this idea, we have previously demonstrated that MKs increase osteoblast (OB) proliferation by a direct cell-cell contact mechanism and that MKs also inhibit osteoclast (OC) formation. As MKs and OCs are derived from the same hematopoietic precursor, in these osteoclastogenesis studies we examined the role of the main MK growth factor, thrombopoietin (TPO) on OC formation and bone resorption. Here we show that TPO directly increases OC formation and differentiation in vitro. Specifically, we demonstrate the TPO receptor (c-mpl or CD110) is expressed on cells of the OC lineage, c-mpl is required for TPO to enhance OC formation in vitro, and TPO activates the mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, and nuclear factor-kappaB signaling pathways, but does not activate the PI3K/AKT pathway. Further, we found TPO enhances OC resorption in CD14+CD110+ human OC progenitors derived from peripheral blood mononuclear cells, and further separating OC progenitors based on CD110 expression enriches for mature OC development. The regulation of OCs by TPO highlights a novel therapeutic target for bone loss diseases and may be important to consider in the numerous hematologic disorders associated with alterations in TPO/c-mpl signaling as well as in patients suffering from bone disorders.
新出现的数据表明，巨核细胞（MKs）在骨骼稳态中发挥着重要作用。事实上，在几种与MK相关的疾病中观察到的骨硬化可能是MK数量增加的结果。支持这一观点的是，我们之前已经证明，MKs通过直接的细胞间接触机制增加成骨细胞（OB）的增殖，并且MKs还抑制破骨细胞（OC）的形成。由于MKs和OCs来源于相同的造血前体，在这些破骨细胞生成研究中，我们研究了主要的MK生长因子血小板生成素（TPO）对OC形成和骨吸收的作用。在这里，我们表明TPO在体外直接增加OC的形成和分化。具体而言，我们证明TPO受体（c-mpl或CD110）在OC谱系的细胞上表达，c-mpl是TPO在体外增强OC形成所必需的，并且TPO激活丝裂原活化蛋白激酶、Janus激酶/信号转导和转录激活因子以及核因子-κB信号通路，但不激活PI3K/AKT通路。此外，我们发现TPO增强了源自外周血单核细胞的CD14+CD110+人OC祖细胞的OC吸收，并且基于CD110表达进一步分离OC祖细胞可促进成熟OC的发育。TPO对OC的调节突出了骨丢失疾病的一个新的治疗靶点，并且在与TPO/c-mpl信号改变相关的众多血液系统疾病以及患有骨疾病的患者中考虑这一点可能很重要。
