Department of Medicine, University of Helsinki/Helsinki University Central Hospital, Helsinki, Finland.
J Rheumatol. 2013 May;40(5):695-702. doi: 10.3899/jrheum.121159. Epub 2013 Mar 15.
Cartilage degeneration in osteoarthritis (OA) leads to release of potential danger signals. The aim of our study was to profile OA cartilage for the Toll-like receptor (TLR) danger signal receptors.
Osteochondral cylinders from total knee replacements were graded using OA Research Society International score and stained for proteoglycans, collagenase-cleaved type II collagen, and TLR 1-10, which were analyzed histomorphometrically.
Grade 1 OA lesions contained 22%-55% TLR 1-9-positive cells in the surface zone, depending on the TLR type. In Grade 2 TLR, immunoreactivity was 60%-100% (p < 0.01) and it was even higher in Grades 3 and 4 (p < 0.01 vs Grade 1). TLR-positive cells in Grade 1 middle zone were low, 0-19.9%, but were 5.1%-32.7% in Grade 2 (p < 0.01) and 34%-83% in Grades 3-4 samples (p < 0.001). TLR values in Grade 5 were low (14.3%-28.7%; p < 0.001). In Grades 3-4 OA, cartilage matrix stained strongly for TLR. In Grade 1, COL2-3/4M was restricted to chondrocytes, but was increasingly seen in matrix upon progress of OA to Grade 4, and then declined.
Cells in the gliding surface zone are fully equipped with TLR in mild OA. Their proportion increases and extends to the middle or even the deep zone, reflecting OA progression. COL2A-3/4M staining suggests Endo180-mediated intake for intralysosomal degradation by cathepsins in Grade 1, but in higher grades this chondrocyte-mediated clearance fails and the matrix demonstrates extensive collagenase-induced damage. Detached and/or partially degraded matrix components can then act as endogenous danger signals (damage-associated molecular patterns or DAMP) and stimulate increasingly TLR-equipped chondrocytes to inflammation. At the peak inflammatory response, soluble TLR may exert negative feedback, explaining in part the low TLR levels in Grade 5 OA.
骨关节炎（OA）中的软骨退变导致潜在危险信号的释放。我们的研究旨在分析 OA 软骨中的 Toll 样受体（TLR）危险信号受体。
使用 OA 研究协会国际评分对全膝关节置换的骨软骨柱进行分级，并对糖胺聚糖、胶原酶切割型 II 型胶原和 TLR1-10 进行染色，然后进行组织形态计量学分析。
根据 TLR 类型的不同，1 级 OA 病变的表面层中 TLR1-9 阳性细胞占 22%-55%。在 2 级 TLR 中，免疫反应性为 60%-100%（p<0.01），在 3 级和 4 级中更高（p<0.01 与 1 级相比）。1 级中层 TLR 阳性细胞较少，0-19.9%，但在 2 级中为 5.1%-32.7%（p<0.01），在 3-4 级样本中为 34%-83%（p<0.001）。5 级 TLR 值较低（14.3%-28.7%；p<0.001）。在 3-4 级 OA 中，软骨基质强烈染色 TLR。在 1 级中，COL2-3/4M 仅限于软骨细胞，但随着 OA 进展到 4 级，在基质中越来越明显，然后下降。
在轻度 OA 中，滑行表面层中的细胞完全配备有 TLR。它们的比例增加并扩展到中层甚至深层，反映 OA 的进展。COL2A-3/4M 染色表明在 1 级中，内体 180 介导的摄取通过组织蛋白酶进行细胞内体降解，但在较高等级中，这种软骨细胞介导的清除失败，基质显示出广泛的胶原酶诱导的损伤。然后，分离的和/或部分降解的基质成分可以作为内源性危险信号（损伤相关分子模式或 DAMP）并刺激越来越多配备 TLR 的软骨细胞发生炎症。在炎症反应的高峰期，可溶性 TLR 可能发挥负反馈作用，部分解释了 5 级 OA 中 TLR 水平较低的原因。
