Cheng Ying-Hua, Streicher Drew A, Waning David L, Chitteti Brahmananda R, Gerard-O'Riley Rita, Horowitz Mark C, Bidwell Joseph P, Pavalko Fredrick M, Srour Edward F, Mayo Lindsey D, Kacena Melissa A
Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
J Cell Physiol. 2015 Mar;230(3):578-86. doi: 10.1002/jcp.24774.
Recent studies suggest that megakaryocytes (MKs) may play a significant role in skeletal homeostasis, as evident by the occurrence of osteosclerosis in multiple MK related diseases (Lennert et al., 1975; Thiele et al., 1999; Chagraoui et al., 2006). We previously reported a novel interaction whereby MKs enhanced proliferation of osteoblast lineage/osteoprogenitor cells (OBs) by a mechanism requiring direct cell-cell contact. However, the signal transduction pathways and the downstream effector molecules involved in this process have not been characterized. Here we show that MKs contact with OBs, via beta1 integrin, activate the p38/MAPKAPK2/p90RSK kinase cascade in the bone cells, which causes Mdm2 to neutralizes p53/Rb-mediated check point and allows progression through the G1/S. Interestingly, activation of MAPK (ERK1/2) and AKT, collateral pathways that regulate the cell cycle, remained unchanged with MK stimulation of OBs. The MK-to-OB signaling ultimately results in significant increases in the expression of c-fos and cyclin A, necessary for sustaining the OB proliferation. Overall, our findings show that OBs respond to the presence of MKs, in part, via an integrin-mediated signaling mechanism, activating a novel response axis that de-represses cell cycle activity. Understanding the mechanisms by which MKs enhance OB proliferation will facilitate the development of novel anabolic therapies to treat bone loss associated with osteoporosis and other bone-related diseases.
最近的研究表明，巨核细胞（MKs）可能在骨骼稳态中发挥重要作用，这在多种与MK相关的疾病中出现的骨硬化现象中得到了证实（Lennert等人，1975年；Thiele等人，1999年；Chagraoui等人，2006年）。我们之前报道了一种新的相互作用，即MKs通过一种需要直接细胞间接触的机制增强成骨细胞谱系/骨祖细胞（OBs）的增殖。然而，参与这一过程的信号转导途径和下游效应分子尚未得到明确。在此，我们表明MKs通过β1整合素与OBs接触，激活骨细胞中的p38/MAPKAPK2/p90RSK激酶级联反应，这导致Mdm2中和p53/Rb介导的检查点，并允许细胞通过G1/S期。有趣的是，调节细胞周期的并行途径MAPK（ERK1/2）和AKT的激活在MK刺激OBs时保持不变。MK与OB之间的信号传导最终导致c-fos和细胞周期蛋白A的表达显著增加，这是维持OB增殖所必需的。总体而言，我们的研究结果表明，OBs部分通过整合素介导的信号机制对MKs的存在做出反应，激活了一个解除细胞周期活性抑制的新反应轴。了解MKs增强OB增殖的机制将有助于开发新的合成代谢疗法，以治疗与骨质疏松症和其他骨相关疾病相关的骨质流失。
