Osteoblast and Osteocyte Dysfunction in Chronic Kidney Disease

慢性肾脏病中的成骨细胞和骨细胞功能障碍

• 批准号: 8637486
• 负责人: KATHERINE WESSELING-PERRY
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637486
• 关键词: Adult; Affect; Aftercare; Animals; Biology; Biopsy; Blood; Bone Diseases; Bone Mineralization Regulation Pathway; Bone Pain; Calcium; Cell Culture Techniques; Cells; Characteristics; Chemosensitization; Child; Childhood; Chronic Kidney Failure; Cleaved cell; Clinical Trials; Culture Media; Data; Defect; Deformity; Development; Disabled Persons; End stage renal failure; Enzymes; Evaluation; Excision; Fracture; Functional disorder; Future; Gelatinase A; Generations; Genetic Transcription; Glycerophosphates; Growth; Harvest; Hormonal; Hormones; Human; In Vitro; Ions; Kidney; Kidney Failure; Knowledge; Libraries; Mechanics; Mediating; Metabolism; Minerals; Modeling; Morbidity - disease rate; Nature; Nodule; Osteoblasts; Osteocytes; Outcome; Pathogenesis; Patients; Phenotype; Phosphorus; Physiologic calcification; Physiological; Plague; Population; Process; Proteins; Relative (related person); Renal Osteodystrophy; Renal function; Reporting; Rodent; Role; Sampling; Secondary Hyperparathyroidism; Somatotropin; Staging; Sterols; Stimulus; Symptoms; System; Testing; Vitamin D; adverse outcome; analog; base; bone; dentin matrix protein 1; effective therapy; fibroblast growth factor 23; handicapping condition; hormone therapy; improved; in vivo; in vivo Model; indexing; mineralization; novel; novel therapeutics; procollagen C-endopeptidase; protein expression; public health relevance; research study; skeletal; skeletal disorder; treatment strategy

DESCRIPTION (provided by applicant): Osteocytes are key regulators of skeletal mineralization and their function is dysregulated in pediatric patients with chronic kidney disease, contributing to such adverse consequences including poor growth, boney deformities, bone pain and fractures. A more complete understanding of osteoblast/osteocyte biology and the process of skeletal mineralization is critical to improving skeletal outcomes. HYPOTHESIS: Osteoblasts harvested from CKD patients have intrinsic abnormalities in mineralization potential and these abnormalities are ameliorated and/or potentiated by changes in circulating hormone concentrations. METHODS: Paired samples of primary osteoblast cells from pediatric patients with stage V chronic kidney disease, obtained before and after active vitamin D sterol therapy, will be used to assess, in vitro, osteoblast maturation and mineralization characteristics and the effects of systemic vitamin D sterol therapy on these characteristics. Subsequently, alterations in mineral and hormonal content will be made to the cell culture media to evaluate the separate effects of these circulating factors on skeletal mineralization. IMPLICATIONS: The current study presents a novel system in which to study the pathophysiology of defective skeletal mineralization. Its advantages are the ability to discriminate whether defective mineralization is due to intrinsic changes in cells of osteoblast/osteocyte lineage, to alterations in extrinsic factrs (changes in media mineral and hormone content), or to a combination of both. These results will yield considerable knowledge which can, in future, be used to develop new therapeutic strategies for the treatment of renal osteodystrophy.

描述（由申请人提供）：骨细胞是骨骼矿化的关键调节因子，其功能在患有慢性肾病的儿科患者中失调，导致生长不良、骨骼畸形、骨痛和骨折等不良后果。更全面地了解成骨细胞/骨细胞生物学和骨骼矿化过程对改善骨骼结局至关重要。假设：从CKD患者中获得的成骨细胞具有内在的矿化潜力异常，这些异常通过循环激素浓度的变化得到改善和/或增强。方法：在活性维生素D甾醇治疗前后获得的来自患有V期慢性肾病的儿科患者的原代成骨细胞的配对样本将用于评估体外成骨细胞成熟和矿化特征以及全身性维生素D甾醇治疗对这些特征的影响。随后，将对细胞培养基进行矿物质和激素含量的改变，以评价这些循环因子对骨骼矿化的单独影响。目前的研究提出了一个新的系统，其中研究有缺陷的骨骼矿化的病理生理学。其优点是能够区分缺陷矿化是否是由于成骨细胞/骨细胞谱系细胞的内在变化，外在因素的改变（介质矿物质和激素含量的变化），或两者的组合。这些结果将产生相当多的知识，在未来，可以用来开发新的治疗策略，治疗肾性骨营养不良。