BMP2 induces osteoblast apoptosis in a maturation state and noggin-dependent manner.
BMP2 induces osteoblast apoptosis in a maturation state and noggin-dependent manner.
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DOI：
10.1002/jcb.24201
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发表时间：
2012-10
影响因子：
4
通讯作者：
Boyan, Barbara D.
中科院分区：
文献类型：
--
作者：
Hyzy, Sharon L.;Olivares-Navarrete, Rene;Schwartz, Zvi;Boyan, Barbara D.
关键词：
大剂量的骨形态发生蛋白2（BMP 2）在临床上用于在具有挑战性的骨缺损中诱导骨形成。然而，治疗后的并发症包括肿胀、异位骨形成和邻近骨吸收。虽然BMP 2可能是有效的，但重要的是表征有害作用的机制以优化其使用。本研究的目的是确定BMP 2对成骨细胞系细胞凋亡的影响，并确定BMP抑制剂Noggin在此过程中的作用。用BMP 2处理人间充质干细胞（MSC）、未成熟成骨细胞样MG 63细胞和成熟正常人成骨细胞（NHOst）。通过沉默头蛋白（shNOG-MG 63）产生内源性BMP信号传导增加的模型系统。最后，使用BMP信号传导抑制剂（5 Z-7-oxozeaenol，dorsomorphin，H-8）检查调节NHOst中细胞凋亡的BMP途径。凋亡的特征是caspase-3，BAX/BCL 2，p53和DNA片段。BMP 2以细胞类型依赖的方式诱导细胞凋亡。虽然在MSC中的作用较小，但在BMP 2处理后，MG 63细胞具有适度的增加，NHOst细胞具有稳健的凋亡增加。shNOG-MG 63细胞凋亡率明显高于MG 63细胞。5 Z-7-oxozeaenol和dorsomorphin消除了NHOst中BMP 2诱导的DNA片段化增加，表明TAB/TAK 1和Smad信号传导的作用。这些结果表明，BMP 2的凋亡作用依赖于细胞成熟状态，通过Smad和TAB/TAK 1信号转导诱导定向成骨细胞凋亡，并受Noggin调节。在BMP 2的治疗应用中必须优化剂量和递送以最小化并发症。
Large doses of bone morphogenetic protein 2 (BMP2) are used clinically to induce bone formation in challenging bone defects. However, complications after treatment include swelling, ectopic bone formation, and adjacent bone resorption. While BMP2 can be effective, it is important to characterize the mechanism of the deleterious effects to optimize its use. The aim of this study was to determine the effect of BMP2 on apoptosis in osteoblast lineage cells and to determine the role of the BMP inhibitor Noggin in this process. Human mesenchymal stem cells (MSCs), immature osteoblast-like MG63 cells, and mature normal human osteoblasts (NHOst) were treated with BMP2. A model system of increased endogenous BMP signaling was created by silencing Noggin (shNOG-MG63). Finally, the BMP pathway regulating apoptosis in NHOst was examined using BMP signaling inhibitors (5Z-7-oxozeaenol, dorsomorphin, H-8). Apoptosis was characterized by caspase-3, BAX/BCL2, p53, and DNA fragmentation. BMP2 induced apoptosis in a cell-type dependent manner. While the effect was minor in MSCs, MG63 cells had modest increases and NHOst cells had robust increases apoptosis after BMP2 treatment. Apoptosis was significantly higher in shNOG-MG63 than MG63 cells. 5Z-7-oxozeaenol and dorsomorphin eliminated the BMP2-induced increase in DNA fragmentation in NHOst, suggesting roles for TAB/TAK1 and Smad signaling. These results indicate that the apoptotic effect of BMP2 is dependent on cell maturation state, inducing apoptosis in committed osteoblasts through Smad and TAB/TAK1 signaling, and is regulated by Noggin. Dose and delivery must be optimized in therapeutic applications of BMP2 to minimize complications.
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