Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, and Orthopaedic Clinic König-Ludwig-Haus, Julius Maximilian University of Würzburg, Würzburg, Germany.
Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Arthritis Rheumatol. 2016 Jul;68(7):1637-47. doi: 10.1002/art.39631.
To test whether intraarticular corticosteroid injection mitigates injury-induced synovitis and collagen degradation after anterior cruciate ligament transection (ACLT) and to characterize the synovial response using a functional genomics approach in a preclinical model of posttraumatic osteoarthritis.
Yorkshire pigs underwent unilateral ACLT without subsequent corticosteroid injection (the ACLT group; n = 6) or ACLT with immediate injection of 20 mg triamcinolone acetonide (the steroid group; n = 6). A control group of pigs (the intact group; n = 6) did not undergo surgery. Total synovial membrane cellularity and synovial fluid concentration of C1,2C neoepitope-bearing collagen fragments 14 days after injury were primary end points and were compared between the ACLT, steroid, and intact groups. Cells were differentiated by histologic phenotype and counted, while RNA sequencing was used to quantify transcriptome-wide gene expression and monocyte, macrophage, and lymphocyte markers.
In the intact group, total cellularity was 13% (95% confidence interval [95% CI] 9-16) and the C1,2C concentration was 0.24 μg/ml (95% CI 0.08-0.39). In the ACLT group, significant increases were observed in total cellularity (to 21% [95% CI 16-27]) and C1,2C concentration (to 0.49 μg/ml [95% CI 0.39-0.59]). Compared to values in the ACLT group, total cellularity in the steroid group was nonsignificantly decreased to 17% (95% CI 15-18) (P = 0.26) and C1,2C concentration in the steroid group was significantly decreased to 0.29 μg/ml (95% CI 0.23-0.35) (P = 0.04). A total of 255 protein-coding transcripts were differentially expressed between the ACLT group and the intact group. These genes mainly enriched pathways related to cellular immune response, proteolysis, and angiogenesis. Mononuclear leukocytes were the dominant cell type in cell-dense areas. MARCO, SOCS3, CCR1, IL4R, and MMP2 expression was significantly associated with C1,2C levels.
Early intraarticular immunosuppression mitigated injury-induced increases in collagen fragments, an outcome better predicted by specific marker expression than by histologic measures of synovitis.
通过在创伤后骨关节炎的临床前模型中使用功能基因组学方法，检测关节内皮质类固醇注射是否减轻前交叉韧带切断（ACLT）后的损伤诱导性滑膜炎和胶原降解，并描述滑膜反应。
约克郡猪接受单侧 ACLT 但不随后进行皮质类固醇注射（ACLT 组；n=6）或 ACLT 后立即注射 20mg 曲安奈德（类固醇组；n=6）。一组猪作为对照组（完整组；n=6）未进行手术。受伤后 14 天的总滑膜膜细胞数和滑膜液中 C1,2C 新表位结合的胶原片段浓度是主要终点，并在 ACLT、类固醇和完整组之间进行比较。通过组织表型分化和计数细胞，同时使用 RNA 测序定量转录组范围的基因表达和单核细胞、巨噬细胞和淋巴细胞标记物。
在完整组中，总细胞数为 13%（95%置信区间 [95%CI] 9-16），C1,2C 浓度为 0.24μg/ml（95%CI 0.08-0.39）。在 ACLT 组中，总细胞数显著增加至 21%（95%CI 16-27），C1,2C 浓度增加至 0.49μg/ml（95%CI 0.39-0.59）。与 ACLT 组相比，类固醇组的总细胞数略有减少，至 17%（95%CI 15-18）（P=0.26），C1,2C 浓度显著减少至 0.29μg/ml（95%CI 0.23-0.35）（P=0.04）。ACLT 组与完整组之间有 255 个蛋白编码转录物差异表达。这些基因主要富集与细胞免疫反应、蛋白水解和血管生成相关的途径。单核白细胞是细胞密集区的主要细胞类型。MARCO、SOCS3、CCR1、IL4R 和 MMP2 的表达与 C1,2C 水平显著相关。
早期关节内免疫抑制减轻了损伤诱导的胶原片段增加，其结果通过特定标记物的表达比通过滑膜炎的组织学测量更好地预测。
