Hruska Keith A, Mathew Suresh, Davies Matthew R, Lund Richard J
Washington University School of Medicine, Renal Division, Department of Pediatrics, St. Louis, MO 63110, USA.
Kidney Int Suppl. 2005 Dec(99):S142-51. doi: 10.1111/j.1523-1755.2005.09926.x.
We have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreases the serum phosphate. Most recently, these observations were rediscovered in low-density lipoprotein receptor null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia, and insulin resistance). We had demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial type. We have shown that VC is worsened by CKD and ameliorated by bone morphogenetic protein -7 (BMP-7). The finding that high-fat-fed low-density lipoprotein receptor null animals without CKD have hyperphosphatemia led us to examine the skeletons of these mice. We found significant reductions in bone formation rates, associated with increased VC and superimposing CKD results in the adynamic bone disorder (ABD), while VC was worsened and hyperphosphatemia persisted. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. BMP-7 treatment corrected the ABD and corrected hyperphosphatemia, compatible with BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. Thus, in the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to ABD producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through increased bone formation and skeletal deposition of phosphate, and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury before demonstrable hyperphosphatemia, and they are preventable and treatable. Therefore, early intervention in CKD is warranted and may affect mortality of the disease.
我们已经表明，肾损伤和慢性肾脏病（CKD）直接抑制骨骼合成代谢，并且刺激骨形成可降低血清磷酸盐水平。最近，在喂食高脂/胆固醇饮食的低密度脂蛋白受体缺失小鼠（一种代谢综合征模型，包括高血压、肥胖、血脂异常和胰岛素抵抗）中重新发现了这些观察结果。我们已经证明，这些小鼠存在内膜动脉粥样硬化型和中膜型的血管钙化（VC）。我们已经表明，CKD会加重VC，而骨形态发生蛋白-7（BMP-7）可改善VC。高脂喂养的无CKD的低密度脂蛋白受体缺失动物出现高磷血症这一发现促使我们检查这些小鼠的骨骼。我们发现骨形成率显著降低，伴有VC增加，叠加CKD会导致动力缺乏型骨病（ABD），而VC会加重且高磷血症持续存在。通过一种对骨骼无作用的磷酸盐结合剂直接降低血清磷酸盐的部分有效性，证明了通过血清磷在异常骨矿化与VC之间存在病理联系。BMP-7治疗纠正了ABD并纠正了高磷血症，这与BMP-7驱动的骨骼磷酸盐沉积刺激降低血浆磷酸盐从而消除对VC的主要刺激作用相一致。因此，在伴有CKD的代谢综合征中，成骨细胞骨形成潜能的降低导致ABD，产生高磷血症和VC，骨骼合成代谢剂BMP-7可改善这些过程，部分是通过增加骨形成和骨骼磷酸盐沉积，部分是通过对血管平滑肌细胞的直接作用。我们已经证明，导致血管钙化的过程在可检测到高磷血症之前甚至在轻度肾损伤时就开始了，并且它们是可预防和可治疗的。因此，对CKD进行早期干预是必要的，并且可能会影响该疾病的死亡率。
