Fibroblast growth factor 23 (FGF23) is a phosphaturic and vitamin D-regulatory hormone that is primarily produced by osteocytes in bone. Circulating levels of this hormone begin to rise at the earliest stages of kidney damage and become markedly elevated with progression of kidney disease. FGF23 not only contributes to mineral and bone abnormalities in patients with CKD, but may also directly induce cardiovascular pathology in this population. Despite substantial evidence linking FGF23 to adverse outcomes, the mechanisms that promote elevated levels of this hormone in CKD remain undefined. Recent reports indicate that patients with CKD exhibit low levels of bacterial endotoxin in their bloodstreams, which may contribute to the inflammatory phenotype that is commonly observed in these patients. While the etiology of this endotoxemia remains unclear, the prevailing hypothesis is that intestinal barrier function is compromised in the setting of kidney injury, allowing endotoxin entry into blood. Interestingly, the pattern of rise for circulating endotoxin levels in CKD mirrors that of FGF23, with modest increments occurring in the early stages of disease and a more dramatic rise in advanced CKD stages. Furthermore, recent observations suggest an independent association between systemic inflammation and FGF23 levels in CKD, possibly implying a pathologic link. It is well-documented that bacterial endotoxin, primarily lipopolysaccharide (LPS), has multiple effects on bone physiology. One of the most established skeletal actions of LPS is a stimulation of bone resorption by promoting osteoclast differentiation via signaling through CD14, a primary LPS co-receptor. Despite a substantial number of studies examining endotoxin effects on osteoblast and osteoclast biology, there is limited published data on LPS effects on osteocytes, the primary cell source for FGF23 production. Preliminary data from our lab suggests that a single injection of LPS in mice stimulates FGF23 gene expression in bone. It remains unclear if this is a direct action on osteocytes in bone or secondary to other systemic actions of LPS. We hypothesize that endotoxemia observed in patients with progressive renal dysfunction contributes to increased FGF23 production by osteocytes in bone in this setting through a CD14-dependent mechanism. We plan to test this hypothesis by: (i) performing both in vitro and in vivo studies to investigate the direct impact of LPS on osteocyte production of FGF23 (Aim 1);(ii) examining the role of CD14 signaling in LPS- mediated FGF23 production by bone by evaluating FGF23 production in CD14-/- mice following LPS injection (Aim 2);and (iii) determining if endotoxemia contributes to the overproduction of FGF23 in CKD through a CD14-dependent mechanism by evaluating FGF23 production by bone from CD14-/- mice following the induction of CKD by adenine ingestion (Aim 3).
Fibroblast growth factor 23 (FGF23) is a novel bone-derived hormone that has been found to regulate phosphorus and vitamin D levels in the body. Blood levels of FGF23 are extremely elevated in patients with chronic kidney disease (CKD) and these high levels are associated with poor outcomes;yet, it remains unclear what is causing the elevated levels of this hormone in this setting. We plan to perform experiments using cell culture techniques and genetically-altered mouse models to test the hypothesis that bacterial toxins present in the bloodstream of patients with CKD may be stimulating FGF23 production by bone.