Polzer Karin, Schett Georg, Zwerina Jochen
Department of Internal Medicine 3, Institute of Clinical Immunology, University of Erlangen, Erlangen, Germany.
Autoimmunity. 2007 Jun;40(4):333-6. doi: 10.1080/08916930701356721.
Inflammatory joint disease typically provokes progressive cartilage damage. The proliferative synovial inflammatory tissue directly invades the cartilage and induces the expression and activation of degrading enzymes such as matrix metalloproteases (MMPs) and aggrecanases. However, also chondrocyte apoptosis has been observed in cartilage samples of inflamed joints. It remains unclear whether this is a secondary phenomenon due to cartilage damage or a primary event initiated by the synovial inflammation. To determine the presence or absence of chondrocyte death in experimental arthritis, we longitudinally assessed proteoglycan depletion and chondrocyte apoptosis in paw sections from human tumor necrosis factor transgenic (hTNFtg) mice and wild-type littermates. Whereas, wild-type mice showed no signs of cartilage damage, hTNFtg mice exhibited progressive proteoglycan loss starting at clinical onset of arthritis. However, we already found the first apoptotic chondrocytes well before cartilage matrix breakdown occurred indicating that chondrocyte death can be induced before matrix resorption. Chondrocyte death could constantly be observed until late stages of arthritis causing a continuous increase in the number of empty cartilage lacunae. As apoptotic cells in cartilage cannot be cleared by phagocytes due to their spatial isolation in the avascular lacunae of cartilage, having no contact to professional or amateur phagocytes. The dying cells are compelled to undergo a "lonely death" inevitable ending up in secondary necrosis giving rise to perpetuation of a pro-inflammatory cascade. These data indicate that chondrocyte death may play a primary role in inflammatory arthritis fueling cartilage inflammation and damage due to secondary necrosis.
炎性关节病通常会引发渐进性软骨损伤。增生性滑膜炎症组织直接侵入软骨，并诱导基质金属蛋白酶（MMPs）和聚集蛋白聚糖酶等降解酶的表达和激活。然而，在炎症关节的软骨样本中也观察到了软骨细胞凋亡。目前尚不清楚这是软骨损伤导致的继发现象，还是滑膜炎症引发的原发性事件。为了确定实验性关节炎中软骨细胞死亡的情况，我们纵向评估了人肿瘤坏死因子转基因（hTNFtg）小鼠和野生型同窝小鼠爪部切片中的蛋白聚糖耗竭和软骨细胞凋亡。野生型小鼠没有软骨损伤的迹象，而hTNFtg小鼠从关节炎临床发作开始就出现了渐进性蛋白聚糖丢失。然而，在软骨基质破坏发生之前，我们就已经发现了第一批凋亡的软骨细胞，这表明软骨细胞死亡可在基质吸收之前被诱导。在关节炎晚期之前，一直可以观察到软骨细胞死亡，导致空软骨陷窝数量持续增加。由于软骨细胞在软骨无血管陷窝中处于空间隔离状态，无法被吞噬细胞清除，与专业或非专业吞噬细胞无接触。垂死的细胞被迫经历“孤独死亡”，最终不可避免地导致继发性坏死，引发促炎级联反应的持续。这些数据表明，软骨细胞死亡可能在炎性关节炎中起主要作用，由于继发性坏死加剧软骨炎症和损伤。
