CARTILAGE-SYNOVIUM INTERACTIONS IN HUMAN ARTHRITIS

类风湿性关节炎的软骨破坏是由于（1）直接 滑膜血管翳侵袭/降解和（2）对可溶性 刺激软骨细胞分解代谢的滑液因子（“分解代谢素”） 活动 这两种机制将在人类关节软骨中进行研究 与类风湿性滑膜或其产物共培养。 蛋白多糖和 胶原蛋白分解和抗风湿药物的反应将是 定量并与采用 牛鼻软骨 从预先标记的软骨中释放的产物将 通过沉淀、色谱和消化方法进行表征。 在滑膜暴露期间和之后，软骨对35 S-硫酸盐的吸收将 评估软骨生物合成的抑制和“修复”能力 活动 滑膜培养物中代谢产物的产生将通过 使用纯化的猪分解代谢产物作为标准品进行软骨盘生物测定。 细胞 相互作用的潜在重要的代谢产物将进行审查 在暴露于凝集素激活的 单核细胞 人和猪分解代谢素的作用将是 在软骨破坏的开始和时间过程方面进行比较， 持续分解代谢产物暴露的要求，降解性质 产品和软骨组织学。 特异性蛋白聚糖酶和胶原酶 活动将寻求在软骨媒体我的手段， 蛋白多糖-胶原混合凝胶分析。 软骨中的早期细胞事件 将在分解代谢素处理软骨中比较上述降解 和软骨细胞培养物。 早期蛋白质和RNA合成的要求 通过在存在或不存在以下物质的情况下掺入前体来测量 抑制剂将与随后的软骨外观相关 酶和分解产物。 糖皮质激素对滑膜的影响 分解代谢产物与软骨分解代谢产物反应，剂量关系 以及激素调节代谢产物的关键时间 功能将被确定。 代谢产物合成的抑制剂研究 释放将扩展到类风湿性滑膜细胞培养， 对影响分解代谢素的单核-滑膜细胞相互作用的影响 生产将进行探索。 澄清这些事件至关重要 了解软骨细胞基础的破坏， 类风湿性病变 反过来，这将有助于设计合理的 药理学和放射疗法以及它们的递送方法。

Cartilage destruction in rheumatoid arthritis results from (1) direct invasion/degradation by synovial pannus and (2) response to a soluble synovial factor(s) ("catabolin") that stimulates chondrocyte catabolic activity. Both mechanisms will be studied in human articular cartilage cocultured with rheumatoid synovium or its products. Proteoglycan and collagen breakdown and the responses to antirheumatic drugs will be quantified and compared to an established heterologous system employing bovine nasal cartilage. Products released from prelabeled cartilage will be characterized by sedimentation, chromatographic and digestion methods. 35S-Sulfate Uptake by cartilage during and after synovium exposure will assess suppression and capacity for "repair" of cartilage biosynthetic activity. Catabolin production in synovial cultures will be assessed by a cartilage disc bioassay using purified porcine catabolin as standard. Cell interactions potentially important in catabolin production will be examined in rheumatoid synovial cell cultures exposed to lectin-activated mononuclear cells. The actions of human and porcine catabolin will be compared in terms of onset and time course of cartilage breakdown, requirement for continued catabolin exposure, nature of degradation products and cartilage histology. Specific proteoglycanase and collagenase activities will be sought in cartilage media my means of a labeled proteoglycan-collagen mixed gel assay. Early cellular events in cartilage that precede degradation will be compared in catabolin-treated cartilage and chondrocyte cultures. Requirements for early protein and RNA synthesis measured by precursor incorporation in the presence or absence of inhibitors will be correlated with the subsequent appearance of cartilage enzymes and breakdown products. Glucocorticoid effects on synovial catabolin production vs. cartilage catabolin response, dose relationships for each and the critical time for hormone action in regulating catabolin function will be determined. Inhibitor studies of catabolin synthesis and release will be extended to rheumatoid synovial cell cultures, and hormone effects on mononuclear-synovial cell interactions affecting catabolin production will be explored. Clarification of these events is essential for understanding the cellular basis of cartilage breakdown in the rheumatoid lesion. In turn, this will help in designing rational pharmacologic and radiation therapies plus methods for their delivery.