成骨细胞内源性糖皮质激素信号转导的转基因破坏不会改变长期 K/BxN 血清转移诱导的关节炎。
Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis.
机构信息
Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia.
Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
出版信息
Arthritis Res Ther. 2023 Aug 4;25(1):140. doi: 10.1186/s13075-023-03112-9.
BACKGROUND
Disruption of glucocorticoid (GC) signaling in osteoblasts results in a marked attenuation of acute antibody-induced arthritis. The role of endogenous GCs in chronic inflammatory arthritis is however not fully understood. Here, we investigated the impact of endogenous GC signaling in osteoblasts on inflammation and bone integrity under chronic inflammatory arthritis by inactivating osteoblastic GC signaling in a long-term K/BxN serum transfer-induced induced arthritis (STIA) model.
METHODS
Intracellular GC signaling in osteoblasts was disrupted by transgenic (tg) overexpression of 11beta-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). Inflammatory arthritis was induced in 5-week-old male tg mice and their wild type (WT) littermates by intraperitoneal (i.p.) injection of K/BxN serum while controls (CTRLs) received phosphate-buffered saline (PBS). In a first cohort, K/BxN STIA was allowed to abate until the endpoint of 42 days (STIA). To mimic rheumatic flares, a second cohort was additionally injected on days 14 and 28 with K/BxN serum (STIA ). Arthritis severity was assessed daily by clinical scoring and ankle size measurements. Ankle joints were assessed histopathologically. Systemic effects of inflammation on long bone metabolism were analyzed in proximal tibiae by micro-computed tomography (μCT) and histomorphometry.
RESULTS
Acute arthritis developed in both tg and WT mice (STIA and STIA ) and peaked around day 8. While WT STIA and tg STIA mice showed a steady decline of inflammation until day 42, WT STIA and tg STIA mice exhibited an arthritic phenotype over a period of 42 days. Clinical arthritis severity did not differ significantly between WT and tg mice, neither in the STIA nor in the STIA cohorts. Correspondingly, histological indices of inflammation, cartilage damage, and bone erosion showed no significant difference between WT and tg mice on day 42. Histomorphometry revealed an increased bone turnover in tg CTRL and tg STIA compared to WT CTRL and WT STIA animals, respectively.
CONCLUSIONS
In contrast to the previously reported modulating effects of endogenous GC signaling in osteoblasts during acute K/BxN STIA, this effect seems to perish during the chronic inflammatory and resolution phase. These findings indicate that endogenous GC signaling in osteoblasts may mainly be relevant during acute and subacute inflammatory processes.
背景
破骨细胞中糖皮质激素（GC）信号的中断导致急性抗体诱导性关节炎明显减弱。然而，内源性 GCs 在慢性炎症性关节炎中的作用尚不完全清楚。在这里，我们通过在长期 K/BxN 血清转移诱导的关节炎（STIA）模型中抑制成骨细胞中的内源性 GC 信号，研究了成骨细胞中内源性 GC 信号对慢性炎症性关节炎下炎症和骨完整性的影响。
方法
通过转基因（tg）过表达 11β-羟类固醇脱氢酶 2（11ß-HSD2）来破坏成骨细胞中的细胞内 GC 信号。通过腹腔内（i.p.）注射 K/BxN 血清在 5 周龄雄性 tg 小鼠及其野生型（WT）同窝仔鼠中诱导炎症性关节炎，而对照组（CTRLs）接受磷酸盐缓冲盐水（PBS）。在第一队列中，允许 K/BxN STIA 减轻，直到第 42 天的终点（STIA）。为了模拟风湿发作，第二队列在第 14 天和第 28 天另外用 K/BxN 血清（STIA）注射。每天通过临床评分和踝关节大小测量评估关节炎严重程度。通过微计算机断层扫描（μCT）和组织形态计量学分析踝关节对长骨代谢的系统炎症影响。
结果
tg 和 WT 小鼠均出现急性关节炎（STIA 和 STIA），并在第 8 天左右达到高峰。虽然 WT STIA 和 tg STIA 小鼠的炎症逐渐减轻，直到第 42 天，但 WT STIA 和 tg STIA 小鼠在 42 天的时间内表现出关节炎表型。WT 和 tg 小鼠在 STIA 和 STIA 队列中的临床关节炎严重程度均无显著差异。相应地，WT 和 tg 小鼠在第 42 天的炎症、软骨损伤和骨侵蚀的组织学指标也无显著差异。组织形态计量学显示，与 WT CTRL 和 WT STIA 动物相比，tg CTRL 和 tg STIA 动物的骨转换增加。
结论
与先前报道的内源性 GC 信号在急性 K/BxN STIA 期间在成骨细胞中调节作用相反，这种作用似乎在慢性炎症和消退阶段消失。这些发现表明，成骨细胞中的内源性 GC 信号可能主要在急性和亚急性炎症过程中相关。
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