title: Stimulation of fibroblast growth factor 23 by metabolic acidosis requires osteoblastic intracellular calcium signaling and prostaglandin synthesis.
abstract: Serum fibroblast growth factor 23 (FGF23) increases progressively in chronic kidney disease (CKD) and is associated with increased mortality. FGF23 is synthesized in osteoblasts and osteocytes; however, the factors regulating its production are not clear. Patients with CKD have decreased renal acid excretion leading to metabolic acidosis (MET). During MET, acid is buffered by bone with release of mineral calcium (Ca) and phosphate (P). MET increases intracellular Ca signaling and cyclooxygenase 2 (COX2)-induced prostaglandin production in the osteoblast, leading to decreased bone formation and increased bone resorption. We found that MET directly stimulates FGF23 in mouse bone organ cultures and primary osteoblasts. We hypothesized that MET increases FGF23 through similar pathways that lead to bone resorption. Neonatal mouse calvariae were incubated in neutral (NTL, pH = 7.44, Pco2= 38 mmHg, [HCO3-] = 27 mM) or acid (MET, pH = 7.18, Pco2= 37 mmHg, [HCO3-] = 13 mM) medium without or with 2-APB (50 μM), an inhibitor of intracellular Ca signaling or NS-398 (1 μM), an inhibitor of COX2. Each agent significantly inhibited MET stimulation of medium FGF23 protein and calvarial FGF23 RNA as well as bone resorption at 48 h. To exclude the potential contribution of MET-induced bone P release, we utilized primary calvarial osteoblasts. In these cells each agent inhibited MET stimulation of FGF23 RNA expression at 6 h. Thus stimulation of FGF23 by MET in mouse osteoblasts utilizes the same initial signaling pathways as MET-induced bone resorption. Therapeutic interventions directed toward correction of MET, especially in CKD, have the potential to not only prevent bone resorption but also lower FGF23 and perhaps decrease mortality.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Rochester School of Medicine, Rochester, New York nancy_krieger@urmc.rochester.edu.
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Krieger
authors.affiliation: Division of Nephrology, Department of Medicine, University of Rochester School of Medicine, Rochester, New York.
authors.forename: David A
authors.initials: DA
authors.lastname: Bushinsky
mesh_terms: D000138:Acidosis / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001862:Bone Resorption; D001896:Boron Compounds; D020013:Calcium Signaling; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D051379:Mice; D009578:Nitrobenzenes; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D061251:Primary Cell Culture; D011453:Prostaglandins / Q000096:biosynthesis; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism; D013449:Sulfonamides
chemical_list: D001896:Boron Compounds; C000717428:Fgf23 protein, mouse; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C109986:2-aminoethoxydiphenyl borate
keywords: FGF23; intracellular Ca; metabolic acidosis; osteoblast; prostaglandins