Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-8883, USA; Sports Medicine, Tenri University, Tenri 632-8510, Japan.
Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
Osteoarthritis Cartilage. 2019 Feb;27(2):326-335. doi: 10.1016/j.joca.2018.10.010. Epub 2018 Nov 4.
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.
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.
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.
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.
青少年股骨头缺血性坏死（JIO）是儿童期最严重的髋关节疾病之一，可导致股骨头永久性畸形。我们最近报道称，白细胞介素 6（IL6）在 JIO 患者的髋关节滑液中明显增加，而关节软骨细胞是 IL6 的主要来源。本研究旨在探讨抑制 IL6 受体是否能改善 JIO 中的软骨保存和骨愈合。
采用 6 周龄小鼠的小型动物模型（即 JIO），用生理盐水或 IL6 受体阻滞剂托珠单抗治疗 6 周。
托珠单抗治疗可减少关节软骨中的 TUNEL 阳性软骨细胞，同时增加软骨基质。在接受托珠单抗治疗的小鼠的关节软骨中，软骨合成标志物 Sox9 的水平显著增加。微 CT 评估显示，托珠单抗治疗可显著增加骺板小梁骨体积（P=0.001，n=10）、厚度（P=0.007）和数量（P=0.014），减少骨分离（P=0.002）及其畸形（P=0.003）。在缺氧条件下，托珠单抗治疗可显著增加人软骨细胞中的骨形成标志物 BMP2 和血管内皮生长因子（VEGF），同时降低骨吸收标志物 RANKL/OPG 比值。
在缺血性坏死发生后应用托珠单抗治疗具有软骨合成作用，并可增加 JIO 小鼠模型中的骨体积。这些发现为使用 JIO 大型动物模型进行托珠单抗的临床前研究和验证这种治疗方法的临床试验提供了可能。
