Acute BMP2 upregulation following induction of immature femoral head ischemic osteonecrosis in
Acute BMP2 upregulation following induction of immature femoral head ischemic osteonecrosis in
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DOI：
10.1016/j.bone.2012.11.023
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发表时间：
2013-03-01
期刊：
影响因子：
4.1
通讯作者：
Kim, Harry K. W.
中科院分区：
文献类型：
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作者：
Kamiya, Nobuhiro;Shafer, Sasha;Kim, Harry K. W.
青少年股骨头缺血性骨坏死(IOFH)是导致股骨头畸形的最严重的髋关节疾病之一。对缺血性骨坏死后的BMP信号转导机制知之甚少。在这项研究中，我们使用我们的未成熟的猪IOFH模型，在缺血诱导后24小时发现股骨头软骨中BMP2的急性上调。同样，在我们的缺血性骨坏死小鼠模型中，BMP2的表达和BMP信号在坏死骨周围的关节软骨中增强。与常氧(21%O-2)相比，低氧(1%O-2)下软骨组织和原代软骨细胞BMP2表达增加。加入缺氧诱导因子1(HIF1)激动剂DFO显著增加BMP2，而HIF1沉默(SiHIF1)仅部分减少BMP2，提示BMP2上调的其他机制存在。众所周知，低氧会诱导氧自由基的产生，而氧自由基会被超氧化物歧化酶2(SOD2)转化为过氧化氢(H2O2)。作为另一种机制，我们研究了过氧化氢/SOD2的产生对BMP2上调的影响。低氧条件下软骨细胞产生的过氧化氢高于常氧条件下的软骨细胞。在软骨细胞培养中加入过氧化氢也能显著增加BMP2的表达。缺氧培养的原代软骨细胞/软骨细胞和术后24小时缺血的猪软骨组织中SOD2的表达也显著增加。在软骨细胞培养中加入Sod2蛋白可显著增加BMP2的表达。此外，DFO显著增加了SOD2，而高保真静音仅部分降低了SOD2。这些结果表明，软骨细胞对缺血性骨坏死的急性BMP2反应更多地是通过H_2O_2产生，仅有部分通过HiFi途径。(C)2012 Elsevier Inc.保留所有权利。
Juvenile ischemic osteonecrosis of the femoral head (IOFH) is one of the most serious hip conditions causing the femoral head deformity. Little is known about BMP signaling following ischemic osteonecrosis. In this study, we found acute BMP2 upregulation in the femoral head cartilage 24 h after ischemic induction using our immature pig IOFH model. Similarly, in our ischemic osteonecrosis mouse model, BMP2 expression and BMP signaling were enhanced in the articular cartilage surrounding the necrotic bone. BMP2 was increased in cartilage explants and primary chondrocytes under hypoxia (1% O-2) compared with normoxia (21% O-2). Addition of the hypoxia inducible factor 1 (HIF1) activator DFO significantly increased BMP2 while HIF1 silencing (siHIF1) only partially reduced BMP2, suggesting other mechanisms of BMP2 upregulation being present. Hypoxia is known to induce the production of free oxygen radicals, which are converted to hydrogen peroxide (H2O2) by superoxide dismutase 2 (SOD2). As an alternative mechanism, we investigated the effect of H2O2/SOD2 production on BMP2 upregulation. Chondrocytes produced more H2O2 under hypoxia than normoxia. H2O2 addition to the chondrocyte culture also significantly increased BMP2 expression. SOD2 was also dramatically increased in the ischemic pig cartilage at 24 h following surgery and in primary chondrocytes/cartilage explants culture under hypoxia. SOD2 protein addition to the chondrocyte culture significantly increased BMP2. Moreover, DFO significantly increased SOD2 while HIFI silencing only partially reduced SOD2. These results suggest that the acute BMP2 response of chondrocytes to ischemic osteonecrosis is more dominantly through the H2O2 production and only partly through the HIFI pathway. (C) 2012 Elsevier Inc. All rights reserved.