Helmholtz Institute for Biomedical Engineering, Biointerface Lab, RWTH Aachen University Hospital, Aachen, Germany.
IZKF Research Group Tissue Regeneration in Musculoskeletal Regeneration, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
PLoS One. 2020 Feb 19;15(2):e0228938. doi: 10.1371/journal.pone.0228938. eCollection 2020.
Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic targets that could be influenced by dietary of parenteral supplementation. We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the Trpm6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with parenteral administration of fetuin-A dietary magnesium supplementation, phosphate restriction, or by or parenteral pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement. We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, magnesium, and pyrophosphate. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, magnesium and pyrophosphate levels.
钙化可破坏心血管系统和肾脏的器官功能，尤其常见于慢性肾脏病 (CKD) 患者。在 DBA/2 遗传背景下维持的缺乏胎球蛋白-A 的小鼠表现出特别严重的软组织钙化，而缺乏胎球蛋白-A 的 C57BL/6 小鼠仍然健康。我们采用分子遗传学分析来鉴定胎球蛋白-A 缺乏小鼠钙化的危险因素。我们试图确定可通过饮食或肠外补充来影响的药物治疗靶点。我们研究了胎球蛋白-A 缺乏的 DBA/2 和 C57BL/6 小鼠杂交后代，以鉴定参与钙化的候选风险基因。我们确定了 Abcc6 基因的一个低功能突变，该基因是一种提供全身焦磷酸盐的肝脏 ATP 转运蛋白，以及肾脏中 Trpm6 镁转运蛋白调节失败，与钙化的严重程度相关。易发生钙化的胎球蛋白-A 缺乏型小鼠分别接受胎球蛋白-A 的肠外给药、饮食镁补充、磷酸盐限制或肠外焦磷酸盐治疗。所有治疗均通过计算机断层扫描、组织学和组织钙测量明显减少软组织钙化。我们表明，胎球蛋白-A 缺乏的 DBA/2 小鼠中的病理性异位钙化是由三种主要细胞外和全身钙化抑制剂（即胎球蛋白-A、镁和焦磷酸盐）的复合缺乏引起的。已知这三种抑制剂都可以单独稳定蛋白质-矿物质复合物，从而抑制细胞外液中矿物质的沉淀。我们首次证明了一种复合三重缺乏症，可通过简单的饮食或肠外补充来治疗。这在患有晚期 CKD 的患者中尤为重要，这些患者通常表现出血清胎球蛋白-A、镁和焦磷酸盐水平降低。
