BIOLOGICAL EFFECTS OF BASIC CALCIUM PHOSPHATE CRYSTALS

描述：（改编自研究者摘要）钙- 含有晶体沉积疾病，包括钙 焦磷酸二水合物和碱性磷酸钙晶体，是一种 一组临床异质性关节炎， 老年人的发病率。关节内含钙结晶 产生假性痛风的急性炎症发作以及 与软骨钙质沉着症相关的慢性退行性关节炎， 密尔沃基肩关节综合征。这些疾病的病因尚不清楚。 由于目前对病理性钙化机制的理解 是有限的，没有可靠的方法存在，以防止钙晶体 沉积或影响再吸收。总体目标是 确定退行性关节病相关的发病机制 这些晶体沉积在关节组织中， 制定合理的手段，防止或扭转 这样的沉积。 这项提案的重点是细胞和钙之间的相互作用 晶体特别强调的是要测试的实验：（1） 确定晶体如何激活细胞反应;（2）评估2 潜在的治疗剂，磷酸柠檬酸盐（PC）和前列腺素 （PG）El.待检验的四个假设是：（1）晶体诱导 巨噬细胞合成和释放细胞因子，例如肿瘤坏死 能增强晶体对滑膜细胞作用的因子-a 和/或诱导软骨细胞分泌导致软骨 退化（旁分泌途径）;（2）晶体激活细胞是由于 晶体表面与细胞膜的物理相互作用;（3） 晶体诱导的金属蛋白酶合成可以从 它是早期细胞反应的结果，例如蛋白质 激酶C激活;（4）PC和PGE 1是潜在的治疗剂 基于对含钙生物效应的了解， 晶体它们对晶体诱导的早期细胞反应的影响 将被审查。一种新型的缓释微载体 将测试PC的输送系统。成纤维细胞，软骨细胞， 巨噬细胞培养物和小鼠进行性关节强直动物模型将 用于研究。

DESCRIPTION: (Adapted from the Investigator's Abstract) Calcium- containing crystal-deposition diseases, which include calcium pyrophosphate dihydrate and basic calcium phosphate crystals, are a group of clinically heterogeneous arthritides which cause significant morbidity in the elderly. Intra-articular calcium-containing crystals produce the acute inflammatory episodes of pseudogout as well as the chronic degenerative arthritis associated with chondrocalcinosis and Milwaukee Shoulder Syndrome. The etiology of these diseases is unknown. As present understanding of the mechanisms of pathologic calcification is limited, no reliable method exists to prevent calcium crystals deposition or to effect resorption. The overall objective is to determine the pathogenesis of the degenerative arthropathies associated with the deposition of these crystals in articular tissues in order to develop a rational means of preventing or reversing the consequences of such deposition. This proposal focuses on the interaction between cells and calcium crystals. Specifically emphasized will be experiments to test: (1) to determine how crystals activate cellular responses; (2) to evaluate 2 potential therapeutic agents, phosphocitrate (PC) and prostaglandin (PG)El. Four hypotheses to be tested are: (1) crystals induce macrophages to synthesize and release cytokines e.g. tumor necrosis factor-a which can reinforce the action of crystals on synoviocytes and/or induce chondrocytes to secrete enzymes leading to the cartilage degeneration (paracrine pathway); (2) cell activation by crystals is due to the physical interaction of crystal surface and cell membrane; (3) crystal-induced metalloproteinase synthesis can be dissociated from mitogenesis and is the result of early cellular responses e.g. protein kinase C activation; (4) PC and PGEl are potential therapeutic agents based on knowledge of the biologic effects of calcium-containing crystals. Their effects on the early crystal-induced cellular responses will be examined. A new form of sustained release microcarriers as a delivery system for PC will be tested. Fibroblast, chondrocyte, and macrophage cultures and a Murine Progressive Ankylosis animal model will be used for the studies.