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BIOLOGICAL EFFECTS OF BASIC CALCIUM PHOSPHATE CRYSTALS

碱式磷酸钙晶体的生物效应

基本信息

批准号：
6764245
负责人：
HERMAN S CHEUNG
金额：
$ 25.62万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 2005-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6764245
关键词：
arthritis biological signal transduction calcium phosphate cell membrane cellular pathology citrates connective tissue enzyme biosynthesis fibroblasts genetic regulatory element metalloendopeptidases physical chemical interaction prostaglandin E tissue /cell culture tissue inhibitor of metalloproteinases transcription factor

项目摘要

The US Census Bureau estimated that 35 million American will be 65 years or older by the Year 2000. Osteoarthritis [OA] and pseudogout are the most common afflictions of aging. Crystalline calcium pyrophosphate dihydrate [CPPD] and basic calcium phosphate [BCP] are the 2 most common forms of pathologic articular mineral. Each occurs frequently in OA joints, and each may be phlogistic, causing acute attacks of pseudogout (CPPD) and acute calcific periarthritis (BCP). The incidence of both calcium crystal arthritides significantly increases with age. The overall objective of this proposal is to determine the pathogenesis of the degenerative arthropathies associated with the deposition of CPPD and BCP crystals in articular tissues with the eventual goal of developing a rational means of preventing or reversing the consequences of such deposition. The paradigm of our work is that crystals can cause the degeneration of articular tissues. Crystals induce fibroblast-like synoviocytes to proliferate and produce metalloproteinases [MMP] and prostaglandins [PG], which eventually cause the degeneration of articular tissues. Phosphocitrate, a specific inhibitor of calcium crystals, reverses the degenerative effects of crystals. We are requesting funding to elucidate the mechanism of interaction of crystals and plasma membrane and the subsequent signal pathways leading the activation of various transcription factors and ultimately MMP synthesis and mitogenesis. The overall Hypothesis is that the interaction of crystals with specific components in plasma membrane resulted in MMP expression primarily through a Ras/ERK 1 and 2 Mitogen-activated Protein Kinase (MAPK)/Serum Response Factor (SRF)/c-fos /AP-1 dependent signaling pathway. New treatment strategies that might ameliorate the degenerative process may ensue from new information about how crystals form and how they exert their biologic effects. We shall test 5 inter-related sub-hypothesis: Hypothesis 1: Cell activation by crystals is due to the physical interaction of crystal surface with specific components of the cell membrane e.g. phospholipid. Hypothesis 2: SRF mediates BCP crystal- induced cell activation. Hypothesis 3: BCP crystals induce MMP-1 via a Ras-dependent p42/44 MAPK signal transduction pathway. Hypothesis 4: There are specific cis elements in the promoter of MMP-1 and -13 that regulates crystal-induced MAP synthesis. Hypothesis 5: There are specific cis elements in the promotor of Tissue Inhibitor of Metalloproteinase (TIMP)-2 that regulate crystal inhibition of TIMP- 2 expression.

美国人口普查局估计，到 2000 年，将有 3500 万美国人达到 65 岁或以上。骨关节炎 [OA] 和假性痛风是最常见的衰老疾病。结晶焦磷酸钙二水合物 [CPPD] 和碱式磷酸钙 [BCP] 是病理性关节矿物质的两种最常见形式。每种疾病都经常发生在 OA 关节中，并且每种疾病都可能是炎性疾病，导致假痛风急性发作 (CPPD) 和急性钙化性关节炎 (BCP)。这两种钙晶体关节炎的发病率都随着年龄的增长而显着增加。该提案的总体目标是确定与 CPPD 和 BCP 晶体在关节组织中沉积相关的退行性关节病的发病机制，最终目标是开发一种合理的方法来预防或逆转此类沉积的后果。我们工作的范例是晶体可以导致关节组织的退化。晶体诱导成纤维样滑膜细胞增殖并产生金属蛋白酶[MMP]和前列腺素[PG]，最终导致关节组织退化。磷酸柠檬酸盐是钙晶体的特异性抑制剂，可逆转晶体的退化效应。我们正在申请资金来阐明晶体和质膜相互作用的机制以及随后导致各种转录因子激活并最终导致 MMP 合成和有丝分裂的信号通路。总体假设是，晶体与质膜中特定成分的相互作用主要通过 Ras/ERK 1 和 2 丝裂原激活蛋白激酶 (MAPK)/血清反应因子 (SRF)/c-fos/AP-1 依赖性信号通路导致 MMP 表达。关于晶体如何形成以及它们如何发挥其生物效应的新信息可能会产生可能改善退行性过程的新治疗策略。我们将测试 5 个相互关联的子假设：假设 1：晶体的细胞激活是由于晶体表面与细胞膜的特定成分（例如细胞膜）的物理相互作用所致。磷脂。假设 2：SRF 介导 BCP 晶体诱导的细胞活化。假设 3：BCP 晶体通过 Ras 依赖性 p42/44 MAPK 信号转导途径诱导 MMP-1。假设4：MMP-1和-13的启动子中存在特定的顺式元件，调节晶体诱导的MAP合成。假设5：金属蛋白酶组织抑制剂(TIMP)-2的启动子中存在特定的顺式元件，调节TIMP-2表达的晶体抑制。