Paloian Neil J, Leaf Elizabeth M, Giachelli Cecilia M
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Kidney Int. 2016 May;89(5):1027-1036. doi: 10.1016/j.kint.2015.12.046. Epub 2016 Mar 9.
Pathologic calcification is a significant cause of increased morbidity and mortality in patients with chronic kidney disease. The precise mechanisms of ectopic calcification are not fully elucidated, but it is known to be caused by an imbalance of procalcific and anticalcific factors. In the chronic kidney disease population, an elevated phosphate burden is both highly prevalent and a known risk factor for ectopic calcification. Here we tested whether osteopontin, an inhibitor of calcification, protects against high phosphate load-induced nephrocalcinosis and vascular calcification. Osteopontin knockout mice were placed on a high phosphate diet for 11 weeks. Osteopontin deficiency together with phosphate overload caused uremia, nephrocalcinosis characterized by substantial renal tubular and interstitial calcium deposition, and marked vascular calcification when compared with control mice. Although the osteopontin-deficient mice did not exhibit hypercalcemia or hyperphosphatemia, they did show abnormalities in the mineral metabolism hormone fibroblast growth factor-23. Thus, endogenous osteopontin plays a critical role in the prevention of phosphate-induced nephrocalcinosis and vascular calcification in response to high phosphate load. A better understanding of osteopontin's role in phosphate-induced calcification will hopefully lead to better biomarkers and therapies for this disease, especially in patients with chronic kidney disease and other at-risk populations.
病理性钙化是慢性肾脏病患者发病率和死亡率增加的重要原因。异位钙化的确切机制尚未完全阐明，但已知是由促钙化和抗钙化因子失衡所致。在慢性肾脏病患者群体中，磷酸盐负荷升高极为普遍，且是已知的异位钙化危险因素。在此，我们测试了钙化抑制剂骨桥蛋白是否能预防高磷负荷诱导的肾钙质沉着症和血管钙化。将骨桥蛋白基因敲除小鼠置于高磷饮食11周。与对照小鼠相比，骨桥蛋白缺乏与磷超载共同导致尿毒症、以大量肾小管和间质钙沉积为特征的肾钙质沉着症以及明显的血管钙化。尽管骨桥蛋白缺乏的小鼠未表现出高钙血症或高磷血症，但它们在矿物质代谢激素成纤维细胞生长因子23方面确实出现了异常。因此，内源性骨桥蛋白在预防高磷负荷引起的磷酸盐诱导的肾钙质沉着症和血管钙化中起关键作用。更好地了解骨桥蛋白在磷酸盐诱导的钙化中的作用有望为这种疾病带来更好的生物标志物和治疗方法，尤其是在慢性肾脏病患者和其他高危人群中。
