Steroid-induced osteonecrosis of the femoral head reveals enhanced reactive oxygen species and hyperactive osteoclasts
Steroid-induced osteonecrosis of the femoral head reveals enhanced reactive oxygen species and hyperactive osteoclasts
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DOI：
10.7150/ijbs.40917
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发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
He, Wei
中科院分区：
文献类型：
--
作者：
Chen, Kai;Liu, Yuhao;He, Wei
激素诱导的股骨头坏死（ONFH）是一种进行性骨疾病，通常导致股骨头塌陷和髋关节功能障碍。破骨细胞活性异常是导致ONFH骨结构完整性丧失和软骨下骨折的重要原因。然而，ONFH中破骨细胞募集和过度活化的病理生理机制仍不完全清楚。我们评估了患者和大鼠ONFH模型中激素诱导的股骨头坏死中活性氧（ROS）水平的变化和随后的破骨细胞改变。与健康的邻近骨相比，人股骨头坏死区域的特征是破骨细胞相关蛋白[组织蛋白酶K和抗酒石酸酸性磷酸酶（TRAP）]的表达显著上调，但抗氧化酶（过氧化氢酶、γ-谷氨酰半胱氨酸合成酶[γ-GCSc]和超氧化物歧化酶1 [SOD 1]）的表达显著下调。此外，TNFSF 11（编码RANKL）/TNFRSF 11B（编码OPG）的比例在坏死骨内增加。结论：甲基强的松龙（MPSL）和咪喹莫特（IMI）诱导的大鼠ONFH模型中，股骨头中观察到明显的骨丢失，归因于TRAP阳性破骨细胞数量增加。此外，通过免疫印迹观察到的抗氧化酶的表达减少伴随着在大鼠ONFH模型中二氢乙锭（DHE）的离体ROS荧光信号增加。因此，本研究支持抗氧化剂可能是一种有前途的治疗途径，通过抑制ROS水平和破骨细胞过度活跃来预防或减轻类固醇诱导的ONFH的进展。
Steroid-induced osteonecrosis of the femoral head (ONFH) is a progressive bone disorder which typically results in femoral head collapse and hip joint dysfunction. It is well-accepted that abnormal osteoclast activity contributes to loss of bone structural integrity and subchondral fracture in ONFH. However, the pathophysiologic mechanisms underlying the recruitment and hyperactivation of osteoclasts in ONFH remain incompletely understood. We assessed the changes of reactive oxygen species (ROS) level and subsequent osteoclast alterations in steroid-induced osteonecrotic femoral heads from both patients and rat ONFH models. When compared with healthy neighboring bone, the necrotic region of human femoral head was characterized by robust up-regulated expression of osteoclast-related proteins [cathepsin K and tartrate-resistant acid phosphatase(TRAP)] but pronounced down-regulation of antioxidant enzymes (catalase, gamma-glutamylcysteine synthetase [gamma-GCSc], and superoxide dismutase 1 [SOD1]). In addition, the ratio of TNFSF11 (encoding RANKL)/TNFRSF11B (encoding OPG) was increased within the necrotic bone. Consistently, in rat ONFH models induced by methylprednisolone (MPSL) and imiquimod (IMI), significant bone loss in the femoral head was observed, attributable to increased numbers of TRAP positive osteoclasts. Furthermore, the decreased expression of antioxidant enzymes observed by immunoblotting was accompanied by increased ex-vivo ROS fluorescence signals of dihydroethidium (DHE) in rat ONFH models. Therefore, this study lends support to the rationale that antioxidant agents may be a promising therapeutic avenue to prevent or mitigate the progression of steroid-induced ONFH by inhibiting ROS level and hyperactive osteoclasts.