Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome.
LDL receptor (LDLR)-null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome, have vascular calcification (VC) worsened by chronic kidney disease (CKD) and ameliorated by bone morphogenetic protein-7 (BMP-7), an efficacious agent in treating animal models of renal osteodystrophy. Here, LDLR-/- high-fat-fed mice without CKD were shown to have significant reductions in bone formation rates, associated with increased VC and hyperphosphatemia. Superimposing CKD resulted in a low turnover osteodystrophy, whereas VC worsened and hyperphosphatemia persisted. BMP-7 treatment corrected the hyperphosphatemia, corrected the osteodystrophy, and prevented VC, compatible with skeletal phosphate deposition leading to reduced plasma phosphate and removal of a major stimulus to VC. A pathologic link between abnormal bone mineralization and VC through the serum phosphorus was supported by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in this model of the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to low bone turnover rates, producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through deposition of phosphate and increased bone formation.
Davies
Matthew R
MR
Department of Medicine, Washington University School of Medicine, Campus Box 8208, 5th Floor MPRB, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Lund
Richard J
RJ
Mathew
Suresh
S
Hruska
Keith A
KA
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001018:Aortic Diseases / Q000473:pathology / Q000517:prevention & control*; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D016723:Bone Remodeling; D001842:Bone and Bones / Q000473:pathology; D002114:Calcinosis / Q000473:pathology / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007674:Kidney Diseases / Q000150:complications* / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010280:Parathyroid Glands / Q000503:physiopathology; D010710:Phosphates / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004041:Dietary Fats; D010710:Phosphates; D011973:Receptors, LDL; D016212:Transforming Growth Factor beta; D002118:Calcium