Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
Bone. 2013 Mar;53(1):239-47. doi: 10.1016/j.bone.2012.11.023. Epub 2012 Dec 3.
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 24h 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 (H(2)O(2)) by superoxide dismutase 2 (SOD2). As an alternative mechanism, we investigated the effect of H(2)O(2)/SOD2 production on BMP2 upregulation. Chondrocytes produced more H(2)O(2) under hypoxia than normoxia. H(2)O(2) addition to the chondrocyte culture also significantly increased BMP2 expression. SOD2 was also dramatically increased in the ischemic pig cartilage at 24h 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 HIF1 silencing only partially reduced SOD2. These results suggest that the acute BMP2 response of chondrocytes to ischemic osteonecrosis is more dominantly through the H(2)O(2) production and only partly through the HIF1 pathway.
幼年股骨头缺血性坏死（IOFH）是导致股骨头变形的最严重髋关节疾病之一。对于缺血性骨坏死后的 BMP 信号通路知之甚少。在这项研究中，我们使用未成熟猪 IOFH 模型发现，缺血诱导后 24 小时，股骨头软骨中 BMP2 急性上调。同样，在我们的缺血性骨坏死小鼠模型中，坏死骨周围的关节软骨中 BMP2 表达和 BMP 信号增强。与常氧（21%O2）相比，软骨外植体和原代软骨细胞在低氧（1%O2）下 BMP2 增加。缺氧诱导因子 1（HIF1）激活剂 DFO 显著增加 BMP2，而 HIF1 沉默（siHIF1）仅部分降低 BMP2，表明存在其他 BMP2 上调机制。众所周知，缺氧会诱导产生游离氧自由基，这些自由基被超氧化物歧化酶 2（SOD2）转化为过氧化氢（H2O2）。作为替代机制，我们研究了 H2O2/SOD2 产生对 BMP2 上调的影响。与常氧相比，低氧下软骨细胞产生更多的 H2O2。H2O2 添加到软骨细胞培养物中也显著增加了 BMP2 的表达。在手术后 24 小时的缺血性猪软骨和低氧下原代软骨细胞/软骨外植体培养物中，SOD2 也显著增加。SOD2 蛋白添加到软骨细胞培养物中也显著增加了 BMP2。此外，DFO 显著增加了 SOD2，而 HIF1 沉默仅部分降低了 SOD2。这些结果表明，软骨细胞对缺血性骨坏死的急性 BMP2 反应更主要是通过 H2O2 的产生，而部分通过 HIF1 途径。
