title: Function and effect of bone morphogenetic protein-7 in kidney bone and the bone-vascular links in chronic kidney disease.
abstract: In two independent and separate studies, we have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreased the serum phosphate. In the first study, the serum Ca PO(4), parathyroid hormone (PTH), and calcitriol were maintained normal after renal ablation in mice, and even mild renal injury equivalent to stage 3 CKD decreased bone formation rates. More recently, these observations were rediscovered in low-density lipoprotein receptor null (LDLR-/-) mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia and insulin resistance). We demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial calcification. We have also shown that VC is made worse by CKD and ameliorated by bone morphogenetic protein-7 (BMP-7). The finding that high-fat fed LDLR-/- animals with CKD had hyperphosphatemia which was prevented in BMP-7-treated animals lead us to examine the skeletons of these mice. It was found that significant reductions in bone formation rates were associated with high-fat feeding, and superimposing CKD resulted in the adynamic bone disorder (ABD), while VC was made worse. The effect of CKD to decrease skeletal anabolism (decreased bone formation rates and reduced number of bone modelling units) occurred despite secondary hyperparathyroidism. The BMP-7 treatment corrected the ABD and hyperphosphatemia, owing to BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. 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. Thus, in the metabolic syndrome with CKD, a reduction in bone forming potential of osteogenic cells leads to the ABD producing hyperphosphatemia and VC, processes ameliorated by 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 affecting the skeleton before demonstrable hyperphosphatemia and that they are preventable and treatable. Therefore, early intervention in the skeletal disorder associated with CKD is warranted and may affect mortality of the disease.
authors.affiliation: Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mathew
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: R
authors.initials: R
authors.lastname: Lund
authors.forename: G
authors.initials: G
authors.lastname: Saab
authors.forename: K A
authors.initials: KA
authors.lastname: Hruska
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism / Q000503:physiopathology; D002114:Calcinosis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D002356:Cartilage / Q000378:metabolism / Q000503:physiopathology; D002454:Cell Differentiation / Q000502:physiology; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D010006:Osteoblasts / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology; D010710:Phosphates / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology; D014652:Vascular Diseases / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D010710:Phosphates; D016212:Transforming Growth Factor beta