Osteoblast and Osteocyte Dysfunction in Chronic Kidney Disease

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脏疾病的儿科患者中失调，导致诸如生长不良、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预后至关重要。假设：从CKD患者身上采集的成骨细胞具有内在的矿化电位异常，这些异常可以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V期慢性肾病儿童患者的原代成骨细胞配对样本，将用于体外评估成骨细胞成熟和矿化特征，以及全身维生素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，以评估这些循环因素对骨骼矿化的单独影响。意义：目前的研究提出了一个新的系统来研究骨骼矿化缺陷的病理生理。它的优点是能够区分矿化缺陷是由于成骨细胞/骨细胞谱系的内在变化，外部因素的改变（介质矿物质和激素含量的变化），还是两者的结合。这些结果将产生相当多的知识，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.