Effects of spermine on osteoblasts during iron deficiency in vitro and in vivo during chronic kidney disease

Chronic kidney disease (CKD), affecting millions worldwide, displays alterations in mineral metabolism ultimately adversely affecting bone integrity, yet the mechanisms remain unclear. Iron deficiency, which can often occur with aging and CKD, is independently associated with bone loss and increased mortality. Indeed, iron is a necessary component for osteoblast differentiation and mineralization. A recent study found that iron deficiency can intrinsically change polyamine concentrations through its impact on synthesis and catabolic pathways. Another study associated a decrease in specific polyamines with increased CKD severity. Furthermore, marrow stromal cells lacking the capacity to synthesize the polyamine spermine having reduced osteogenic mineralization. The purpose of this study was to assess the effects of polyamine supplementations during iron deficiency both in vitro and in vivo. We used mouse progenitor cells differentiated under standard osteogenic protocols in the presence of the iron chelator deferoxamine (DFO) with or without spermine supplementation. Iron deficiency negatively impacted mineralization which was reversed with spermine supplementation. In vivo, CKD was induced with 0.2% adenine-containing diet, with adenine-fed subgroups receiving spermine in the drinking water for four to eight weeks. Oral spermine supplementation exhibited a negative effect with no improvements in bone RNA expression, additional bone loss, and a dose dependent decrease in circulating intact fibroblast growth factor 23 (iFGF23). Ultimately, adenine-fed mice supplemented with the highest concentrations of spermine exhibited incidence of heart calcifications which were absent from the vehicle control adenine-fed mice. These data suggest polyamines are potential modulators of mineral metabolism especially in the setting of chronic kidney disease.