Bone Research Program, Australian and New Zealand Army Corps (ANZAC) Research Institute, Sydney, New South Wales, Australia;
Adrenal Steroid Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Sydney, New South Wales, Australia.
FASEB J. 2018 Jan;32(1):478-487. doi: 10.1096/fj.201700659R. Epub 2017 Sep 19.
Previous studies demonstrated that endogenous glucocorticoid signaling in osteoblasts promotes inflammation in murine immune arthritis. The current study determined whether disruption of endogenous glucocorticoid signaling in chondrocytes also modulates the course and severity of arthritis. Tamoxifen-inducible chondrocyte-targeted glucocorticoid receptor-knockout (chGRKO) mice were generated by breeding GR mice with tamoxifen-inducible collagen 2a1 Cre (Col2a1-CreER) mice. Antigen-induced arthritis (AIA) and K/BxN serum transfer-induced arthritis (STIA) were induced in both chGRKO mice and their Cre-negative GR littermates [wild type (WT)]. Arthritis was assessed by measurement of joint swelling and histology of joints collected at d 14. Neutrophil activity and gene expression patterns associated with cartilage damage were also evaluated. In both arthritis models clinical (joint swelling) and histologic indices of inflammatory activity were significantly greater in chGRKO than in WT mice. The STIA model was characterized by early up-regulation of CXCR2/CXCR2 ligand gene expression in ankle tissues, and significant and selective expansion of splenic CXCR2 neutrophils in chGRKO arthritic compared to WT arthritic mice. At later stages, gene expression of enzymes involved in cartilage degradation was up-regulated in chGRKO but not WT arthritic mice. Therefore, we summarize that chondrocytes actively mitigate local joint inflammation, cartilage degradation and systemic neutrophil activity a glucocorticoid-dependent pathway.-Tu, J., Stoner, S., Fromm, P. D., Wang, T., Chen, D., Tuckermann, J., Cooper, M. S., Seibel, M. J., Zhou, H. Endogenous glucocorticoid signaling in chondrocytes attenuates joint inflammation and damage.
先前的研究表明，成骨细胞中的内源性糖皮质激素信号促进了鼠类免疫性关节炎中的炎症反应。本研究旨在确定软骨细胞中内源性糖皮质激素信号的破坏是否也会调节关节炎的病程和严重程度。通过将糖皮质激素受体（GR）小鼠与他莫昔芬诱导型胶原 2a1 Cre（Col2a1-CreER）小鼠杂交，生成了软骨细胞靶向糖皮质激素受体敲除（chGRKO）小鼠。在 chGRKO 小鼠及其 Cre 阴性 GR 同窝仔鼠（野生型（WT））中诱导抗原诱导性关节炎（AIA）和 K/BxN 血清转移诱导性关节炎（STIA）。在第 14 天收集关节肿胀和关节组织学评估关节炎。还评估了与软骨损伤相关的中性粒细胞活性和基因表达模式。在两种关节炎模型中，chGRKO 小鼠的临床（关节肿胀）和组织学炎症活动指标均明显高于 WT 小鼠。STIA 模型的特征是踝组织中 CXCR2/CXCR2 配体基因表达的早期上调，以及 chGRKO 关节炎小鼠与 WT 关节炎小鼠相比，脾脏 CXCR2 中性粒细胞的显著选择性扩增。在后期，chGRKO 关节炎小鼠而非 WT 关节炎小鼠中软骨降解相关酶的基因表达上调。因此，我们总结认为，软骨细胞通过糖皮质激素依赖途径积极减轻局部关节炎症、软骨降解和全身中性粒细胞活性。
