Mineralization and the Role of Matrixphosphoglycoprotein

基质磷酸糖蛋白的矿化和作用

• 批准号: 6789566
• 负责人: PETER S ROWE
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789566
• 关键词: bone; clinical research; extracellular matrix proteins; glycoproteins; human tissue; laboratory mouse; laboratory rat; metalloendopeptidases; normal ossification; odontoblasts; osteoblasts; pathologic ossification; pathologic process; peptides; phosphoproteins; protein protein interaction; protein quantitation /detection; protein sequence; protein structure; protein structure function; tooth; vitamin D resistant rickets

DESCRIPTION (provided by applicant): X-linked hypophosphatemic rickets (HYP) is associated with severe defects in renal phosphate handling, vitamin D metabolism and mineralization. Understanding the pathophysiology of bone-mineral/renal loss disorders is prerequisite to effective treatment of HYP, periodontal disease, tumor induced osteomalacia, renal-stones, osteoporosis, ectopic-calcifications and renal dysfunction. We have substantive preliminary data that supports the hypothesis that mineralization in teeth and bone is regulated by a protein-protein interaction between MEPE (a matrix extracellular phosphoglycoprotein markedly elevated in HYP) and PHEX (a Zn-metalloendopeptidase defective in HYP). The MEPE-PHEX protein-protein interaction protects MEPE from proteolytic cleavage by proteases markedly elevated in HYP (notably cathepsin B). Osteoblast and odontoblast secreted-MEPE in the absence of PHEX is proteolytically cleaved, releasing a phosphorylated, acidic-aspartate-serine-rich, COOH-terminal MEPE-fragment (ASARM-peptide). The ASARM-peptide (2 kDa) is remarkably resistant to a vast array of proteases resulting in increased levels in Hyp. The ASARM-peptide inhibits mineralization and is a negative modulator of normal mineralization and elevated ASARM-peptide is wholly or in part responsible for the mineralization defects in HYP. This proposal will specifically focus on the role of MEPE and ASARM-peptides in mineralization in disease and health. Our specific aims will be: 1. Structural characterization and quantification of MEPE ASARM-peptide(s) in-vitro and in-vivo in normal and Hyp-mouse osteoblasts and HYP patient-serum. 2. Determination of MEPE ASARM-peptide effects on mineralization in-vitro and in-vivo (rats). The ASARM-motif is present in a number of tooth-bone matrix and salivary proteins (MEPE, dentin-matrix-protein-1, osteopontin, statherin, dentin-sialo-phosphoprotein, etc.) that all map to chromosome 4q21. Thus, the elucidation of its role in mineralization is of prime importance for understanding tooth and bone development. Importantly, the part the motif plays in the multiple functions of MEPE will have relevance to the treatment and understanding of periodontal disease, oncogenic hypophosphatemic osteomalacia (OHO), HYP, osteoporosis and disorders of mineralization in teeth, bone, renal-stones and arteries.

描述（由申请人提供）：X连锁低磷血症性佝偻病（HYP）与肾磷酸盐处理、维生素D代谢和矿化的严重缺陷相关。了解骨矿物质/肾损失疾病的病理生理学是有效治疗HYP、牙周病、肿瘤引起的骨软化、肾结石、骨质疏松症、异位钙化和肾功能不全的先决条件。我们有实质性的初步数据支持这一假设，即牙齿和骨骼中的矿化是由MEPE（一种基质细胞外磷酸糖蛋白，在HYP中显著升高）和PHEX（一种Zn-金属内肽酶，在HYP中有缺陷）之间的蛋白质-蛋白质相互作用调节的。MEPE-PHEX蛋白-蛋白相互作用保护MEPE免受HYP中显著升高的蛋白酶（尤其是组织蛋白酶B）的蛋白水解切割。成骨细胞和成牙本质细胞分泌的MEPE在没有PHEX的情况下被蛋白水解切割，释放磷酸化的、富含酸性天冬氨酸丝氨酸的COOH末端MEPE片段（ASARM肽）。ASARM-肽（2 kDa）对大量蛋白酶具有显著抗性，导致Hyp水平升高。ASARM-肽抑制矿化，并且是正常矿化的负调节剂，并且升高的ASARM-肽是HYP中矿化缺陷的全部或部分原因。该提案将特别关注MEPE和ASARM肽在疾病和健康矿化中的作用。我们的具体目标是：1。MEPE ASARM-肽在正常和Hyp-mouse成骨细胞和HYP患者血清中的体外和体内结构表征和定量。2. MEPE ASARM肽对体外和体内矿化作用的测定（大鼠）。ASARM基序存在于许多牙-骨基质和唾液蛋白中（MEPE、牙本质基质蛋白-1、骨桥蛋白、唾液酸蛋白、牙本质唾液酸磷蛋白等）。都对应于染色体4 q21因此，阐明其在矿化中的作用对于理解牙齿和骨骼发育至关重要。重要的是，该基序在MEPE的多种功能中所起的作用将与牙周病、致癌性低磷酸盐血症性骨软化症（OHO）、HYP、骨质疏松症以及牙齿、骨、肾结石和动脉中的矿化障碍的治疗和理解相关。