Bone Marrow Cells Inhibit BMP-2-Induced Osteoblast Activity in the Marrow Environment
Bone Marrow Cells Inhibit BMP-2-Induced Osteoblast Activity in the Marrow Environment
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DOI：
10.1002/jbmr.3598
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发表时间：
2019-02-01
影响因子：
6.2
通讯作者：
Kuboki, Takuo
中科院分区：
文献类型：
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作者：
Ha Thi Nguyen;Ono, Mitsuaki;Kuboki, Takuo
骨形态发生蛋白2（BMP-2）被广泛认为是促进骨形成的有效生长因子。然而，越来越多的研究已经证明了BMP-2治疗的副作用。更深入地了解BMP-2对直接参与骨重建的细胞以外的细胞的作用对于促进BMP-2更有效地递送至患者具有根本重要性。在这项研究中，我们的目的是研究BMP-2在骨髓环境中的作用。首先，将吸附在钛植入物上的BMP-2递送到拔牙窝（骨髓缺失部位）或比格犬的下颌骨骨髓中。BMP-2可诱导拔牙窝处种植体周围明显的骨形成。然而，令人惊讶的是，在插入下颌骨骨髓中的BMP-2涂层钛植入物中没有观察到骨形成。在C57 BL/6小鼠中，BMP-2吸附在冻干胶原颗粒中可以诱导无骨髓颅骨中的骨形成。然而，与犬模型相似，BMP-2不能诱导股骨骨髓中的骨形成。使用Col 1a 1（2.3）-GFP转基因小鼠进行的成骨细胞分化分析显示，BMP-2处理的股骨中成骨细胞数量稀少，而在对照组中，成骨细胞丰富。股骨骨髓消融恢复了BMP-2诱导骨形成的能力。体外实验分析了C2 C12细胞的荧光素酶活性与BMP-反应元件和MC 3 T3-E1成骨细胞的碱性磷酸酶活性，进一步揭示了骨髓细胞通过直接细胞-细胞接触抑制BMP-2对成骨细胞的作用。总的来说，这些结果表明，BMP-2在诱导骨形成中的作用被骨髓细胞通过与成骨细胞的直接细胞-细胞接触显著抑制;这为阐明与BMP-2应用相关的副作用开辟了新的视角。(c)2018年美国骨与矿物质研究学会。
Bone morphogenetic protein 2 (BMP-2) is widely known as a potent growth factor that promotes bone formation. However, an increasing number of studies have demonstrated side effects of BMP-2 therapy. A deeper understanding of the effect of BMP-2 on cells other than those involved directly in bone remodeling is of fundamental importance to promote a more effective delivery of BMP-2 to patients. In this study, we aimed to investigate the effect of BMP-2 in the marrow environment. First, BMP-2 adsorbed onto titanium implants was delivered at the tooth extraction socket (marrow-absent site) or in the mandible marrow of beagle dogs. BMP-2 could induce marked bone formation around the implant at the tooth extraction socket. Surprisingly, however, no bone formation was observed in the BMP-2-coated titanium implants inserted in the mandible marrow. In C57BL/6 mice, BMP-2 adsorbed in freeze-dried collagen pellets could induce bone formation in marrow-absent calvarial bone. However, similar to the canine model, BMP-2 could not induce bone formation in the femur marrow. Analysis of osteoblast differentiation using Col1a1(2.3)-GFP transgenic mice revealed a scarce number of osteoblasts in BMP-2-treated femurs, whereas in the control group, osteoblasts were abundant. Ablation of femur marrow recovered the BMP-2 ability to induce bone formation. In vitro experiments analyzing luciferase activity of C2C12 cells with the BMP-responsive element and alkaline phosphatase activity of MC3T3-E1 osteoblasts further revealed that bone marrow cells inhibit the BMP-2 effect on osteoblasts by direct cell-cell contact. Collectively, these results showed that the effect of BMP-2 in inducing bone formation is remarkably repressed by marrow cells via direct cell-cell contact with osteoblasts; this opens new perspectives on the clarification of the side-effects associated with BMP-2 application. (c) 2018 American Society for Bone and Mineral Research.