CARTILAGE-SYNOVIUM INTERACTIONS IN HUMAN ARTHRITIS

类风湿性关节炎软骨破坏的直接原因是(1) 滑膜血管疙瘩的侵袭/降解和(2)对可溶物的反应 促进软骨细胞分解代谢的滑膜因子(S)(“分解代谢”) 活动。这两种机制都将在人类关节软骨中进行研究。 与类风湿滑膜或其产品共培养。蛋白多糖和 胶原分解和抗风湿药物的反应将是 量化并与已建立的异源系统进行比较 牛鼻软骨。从预先标记的软骨中释放的产品将 用沉淀法、层析法和消化法进行表征。 滑膜暴露期间和之后软骨对35S-硫酸盐的摄取将 评估软骨生物合成的抑制和“修复”能力 活动。滑膜培养中分解代谢产物的产生将通过一项 以纯化的猪分解代谢蛋白为标准进行软骨盘生物测定。细胞 对分解代谢素生产中可能重要的相互作用进行研究。 凝集素激活的类风湿滑膜细胞培养 单个核细胞。人和猪的分解代谢作用将是 在软骨破裂的开始和时间过程方面进行比较， 持续接触分解代谢素的要求、降解的性质 产品和软骨组织学。特异性蛋白聚糖酶和胶原酶 活动将在软骨介质中寻求我的一种标示方式 蛋白多糖-胶原混合凝胶试验。软骨中的早期细胞事件 在分解代谢素治疗的软骨中，将比较在降解之前的那些 和软骨细胞培养。蛋白质和核糖核酸早期合成的需要 以前体在存在或不存在的情况下并入来衡量 抑制物将与随后软骨的出现相关。 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反应的剂量关系 每种激素在调节分解代谢中作用的临界时间 功能将被确定。分解代谢素合成及抑制物研究进展 释放将扩展到类风湿滑膜细胞培养，激素 单核-滑膜细胞相互作用对分解代谢的影响 将探索生产。澄清这些事件是至关重要的 为了了解软骨破裂的细胞学基础 风湿性皮损。反过来，这将有助于设计Rational 药理和放射疗法加上它们的输送方法。

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.