Osteoblast and Osteocyte Dysfunction in Chronic Kidney Disease

描述(申请人提供)：骨细胞是骨骼矿化的关键调节者，其功能在慢性肾脏疾病的儿科患者中调节失调，导致不良后果，包括生长不良、骨畸形、骨痛和骨折。更全面地了解成骨细胞/骨细胞生物学和骨骼矿化过程是改善骨骼预后的关键。假设：从CKD患者获取的成骨细胞具有内在的矿化潜力异常，这些异常可以通过循环激素浓度的变化来改善和/或增强。方法：收集V期慢性肾脏病患儿的成骨细胞，采用活性维生素D类固醇治疗前后的原代成骨细胞标本，分析成骨细胞的成骨和矿化特征，以及维生素D类固醇治疗对成骨细胞成骨和矿化的影响。随后，将对细胞培养液中的矿物质和激素含量进行改变，以评估这些循环因素对骨骼矿化的单独影响。本研究提供了一种新的系统来研究骨骼矿化缺陷的病理生理学。它的优点是能够区分矿化缺陷是由于成骨细胞/骨细胞系细胞的内在变化，还是由于外部因素的变化(介质矿物和激素含量的变化)，还是两者的结合。这些结果将产生大量的知识，这些知识可以在未来用于开发治疗肾性骨营养不良的新治疗策略。

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.