BIOLOGICAL EFFECTS OF BASIC CALCIUM PHOSPHATE CRYSTALS

描述：（改编自研究者的摘要）钙- 含有晶体沉积疾病，其中包括钙 二水焦磷酸盐和碱式磷酸钙晶体，是 一组具有显着临床异质性的关节炎 老年人发病。关节内含钙晶体 产生假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和 密尔沃基肩综合症。这些疾病的病因尚不清楚。 目前对病理钙化机制的了解 是有限的，没有可靠的方法来防止钙结晶 沉积或影响吸收。总体目标是 确定相关退行性关节病的发病机制 这些晶体沉积在关节组织中，以便 制定合理的方法来预防或扭转后果 这样的沉积。 该提案重点关注细胞和钙之间的相互作用 晶体。特别强调将通过实验来测试：（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）埃尔。需要检验的四个假设是：（1）晶体诱导 巨噬细胞合成和释放细胞因子，例如肿瘤坏死 因子-a 可以增强晶体对滑膜细胞的作用 和/或诱导软骨细胞分泌导致软骨形成的酶 变性（旁分泌途径）； (2) 晶体的细胞活化作用是由于 晶体表面和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 有丝分裂是早期细胞反应的结果，例如蛋白质 激酶C激活； (4) PC和PGE1是潜在的治疗药物 基于对含钙生物效应的了解 晶体。它们对早期晶体诱导的细胞反应的影响 将接受检查。一种新型缓释微载体 PC 传输系统将进行测试。成纤维细胞、软骨细胞和 巨噬细胞培养物和小鼠进行性强直动物模型将 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.