Role of disrupted polyamine synthesis during CKD-MBD related bone loss

点击翻译按钮获取中文摘要

Project Summary/Abstract: Bone fragility increasing fracture risk is one of the defining components of mineral and bone disorder of chronic kidney disease (CKD-MBD). Dysregulated bone homeostasis in CKD is significantly linked with morbidity and mortality as patients with CKD that sustain a fracture exhibit higher mortality rates. Additionally, inability to maintain normal bone homeostasis contributes to elevated circulating calcium and phosphorus and development of vascular calcifications. The adenine-diet induced model of renal failure in mice exhibit pathogenic bone alterations parallel to CKD patient bone biopsies including porosity and elevated osteoclasts number. These histological features occur in conjunction with development of iron deficiency anemia, a frequent occurrence during CKD. However, the direct effects of disrupted iron handling on bone homeostasis during renal failure remain unclear. Previous studies have found iron deficiency blunts bone formation both in calvaria osteoblasts and in rodents fed an iron deficient diet. Recent studies have found that iron deficiency alters cellular polyamine synthesis ultimately reducing spermine and spermidine content. Both spermine and spermidine have been found to be important for osteoblast differentiation and function Interestingly, patients with CKD have also been observed to have reduced spermine levels compared to controls. The unifying hypothesis of this proposal is osteoblast differentiation is impaired in CKD-MBD and critical portions of this pathophysiology are mediated by iron deficiency reduced polyamine synthesis. We address this novel avenue of research with two specific aims in this Stephen I. Katz Early Stage Investigator Research Grant. In Aim 1, we will test the hypothesis that iron-deficiency mediated reduction in spermine inhibits osteoblast differentiation. This will be accomplished by assessing spermine supplementation during iron deficiency conditions both in vitro and in vivo. Previous studies indicate that iron deficiency may blunt spermine conversion by reducing spermine synthase. Thus, we will also examine the bone protective transgenic upregulation of spermine synthase during iron deficiency of CKD. Finally, to determine how these small molecules alter gene expression, we will undertake epigenetic sequencing studies as both iron deficiency and polyamines have been postulated to be involved in changes in DNA accessibility. In Aim 2 we will test the hypothesis that iron deficiency of CKD promotes polyamine catabolism at the cellular and systemic level. In patient studies, CKD serum is found to have elevated spermine oxidase activity compared to controls. Additionally, iron deficiency can increase N-acetyltransferase protein levels that catabolize spermine. We will undertake genetic and pharmacological inhibition of during iron deficiency of CKD to address these novel questions. Completion of these studies will significantly enhance our understanding of bone homeostasis in the context of CKD. Our studies will also have important therapeutic implications in regards to interventions for iron deficiency and CKD-MBD.