IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice
IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice
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DOI：
10.1016/j.joca.2018.10.010
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发表时间：
2019-02-01
影响因子：
7
通讯作者：
Kim, H. K. W.
中科院分区：
文献类型：
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作者：
Kamiya, N.;Kuroyanagi, G.;Kim, H. K. W.
目的：儿童缺血性股骨头坏死（JIO）是导致儿童股骨头永久性畸形的最严重的髋关节疾病之一。我们最近报道了白细胞介素6 （IL6）在JIO患者的髋关节滑液中显著升高，关节软骨细胞是IL6的主要来源。本研究探讨il - 6受体的抑制是否能改善JIO的软骨保存和骨愈合。方法：用生理盐水或il - 6受体阻滞剂tocilizumab治疗JIO小动物模型（即6周龄小鼠）6周。结果：托珠单抗治疗后关节软骨中tunel阳性软骨细胞减少，同时软骨基质增加。在托珠单抗治疗的小鼠关节软骨中，软骨合成代谢标志物Sox9的水平显著增加。显微ct评估显示，tocilizumab治疗显著增加了小梁骨量（P = 0.001, n = 10）、厚度（P = 0.007）和数量（P = 0.014），减少了骨分离（P = 0.002）及其畸形（P = 0.003）。使用人软骨细胞在缺氧条件下接受托珠单抗治疗后，骨形成标志物BMP2和血管生成标志物血管内皮生长因子（VEGF）均显著升高，而骨吸收标志物RANKL/OPG比值降低。结论：Tocilizumab治疗缺血性骨坏死小鼠JIO模型具有软骨合成代谢作用，增加骨体积。这一发现可能导致tocilizumab应用于临床前研究，使用大型JIO动物模型和临床试验来验证这种治疗。(c) 2018年国际骨关节炎学会；Elsevier Ltd.出版。版权所有。
Objective: Juvenile ischemic osteonecrosis (JIO) of the femoral head is one of the most serious hip disorders causing a permanent deformity of the femoral head in childhood. We recently reported that interleukin 6 (IL6) is predominantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL6. This study investigated whether an inhibition of IL6 receptor improves cartilage preservation and bone healing in JIO.Method: A small animal model (i.e., 6-week-old mouse) of JIO was treated with either saline or tocilizumab, an IL6 receptor blocker, for 6 weeks.Results: TUNEL-positive chondrocytes in the articular cartilage were reduced by the tocilizumab treatment, concomitant with the increase in cartilage matrix. The levels of a cartilage anabolic marker Sox9 was significantly increased in the articular cartilage of mice treated with tocilizumab. Micro-CT assessment showed tocilizumab treatment significantly increased trabecular epiphyseal bone volume (P = 0.001, n = 10), thickness (P = 0.007) and number (P = 0.014) and decreased bone separation (P = 0.002) and its deformity (P = 0.003). A bone formation marker, BMP2, and an angiogenic marker, vascular endothelial growth factor (VEGF), were both significantly increased by tocilizumab treatment under hypoxia using human chondrocytes while the bone resorption marker, RANKL/OPG ratio, was reduced.Conclusion: Tocilizumab treatment following ischemic osteonecrosis has cartilage anabolic effect and increases bone volume in JIO mouse model. The findings lead to a possible application of tocilizumab for preclinical study using a large animal model of JIO and a clinical trial to validate this treatment. (c) 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.