Kohri Kenjiro, Yasui Takahiro, Okada Atsushi, Hirose Masahito, Hamamoto Shuzo, Fujii Yasuhiro, Niimi Kazuhiro, Taguchi Kazumi
Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
Urol Res. 2012 Dec;40(6):623-37. doi: 10.1007/s00240-012-0514-y. Epub 2012 Nov 6.
Urinary stones consist of two phases-an inorganic (mineral) phase and an organic (matrix) phase. Studies on the organic components of kidney stones have been undertaken later than those on the inorganic components. After osteopontin was identified as one of the matrix components, the biomolecular mechanism of urinary stone formation became clearer. It also triggered the development of new preventive treatments. Osteopontin expression is sporadically observed in normal distal tubular cells and is markedly increased in stone-forming kidneys. Calcium oxalate crystals adhering to renal tubular cells are incorporated into cells by the involvement of osteopontin. Stimulation of crystal-cell adhesion impairs the opening of mitochondrial permeability transition pores (mPTP) in tubular cells and produces oxidative stress, apoptosis, and osteopontin expression. Macrophages phagocytose and digest a small amount of crystals, but many crystals aggregate into a mass containing osteopontin and epithelial cell debris and are excreted into the renal tubular lumen, becoming nuclei of urinary stones. This biomolecular mechanism is similar to atherosclerotic calcification. Based on these findings, new preventive treatments have been developed. Dietary control such as low-cholesterol intake and the ingestion of antioxidative foods and vegetables have successfully reduced the 5-year recurrence rate. Osteopontin antibodies and cyclosporine A, which blocks the opening of mPTP, have markedly inhibited the expression of osteopontin and urinary stone formation in animal models.
尿结石由两个阶段组成——无机（矿物质）阶段和有机（基质）阶段。对肾结石有机成分的研究比对无机成分的研究开展得晚。骨桥蛋白被确定为基质成分之一后，尿结石形成的生物分子机制变得更加清晰。这也引发了新的预防治疗方法的发展。骨桥蛋白表达在正常远端肾小管细胞中偶尔可见，而在结石形成的肾脏中显著增加。草酸钙晶体黏附于肾小管细胞，并通过骨桥蛋白的参与被细胞摄取。晶体-细胞黏附的刺激会损害肾小管细胞中线粒体通透性转换孔（mPTP）的开放，并产生氧化应激、细胞凋亡和骨桥蛋白表达。巨噬细胞吞噬并消化少量晶体，但许多晶体聚集成含有骨桥蛋白和上皮细胞碎片的团块，并排泄到肾小管腔中，成为尿结石的核心。这种生物分子机制与动脉粥样硬化钙化相似。基于这些发现，已开发出新的预防治疗方法。饮食控制，如低胆固醇摄入以及摄入抗氧化食物和蔬菜，已成功降低了5年复发率。骨桥蛋白抗体和可阻断mPTP开放的环孢素A在动物模型中显著抑制了骨桥蛋白的表达和尿结石形成。
