Metabolic acidosis increases fibroblast growth factor 23 in neonatal mouse bone

Abstract

Fibroblast growth factor 23 (FGF23) significantly increases with declining renal function, leading to reduced renal tubular phosphate reabsorption, decreased 1,25-dihydroxyvitamin D, and increased left ventricular hypertrophy. Elevated FGF23 is associated with increased mortality. FGF23 is synthesized in osteoblasts and osteocytes; however, the mechanisms by which it is regulated are not clear. Patients with chronic kidney disease have decreased renal acid excretion leading to metabolic acidosis, which has a direct effect on bone cell activity. We hypothesized that metabolic acidosis would directly increase bone cell FGF23 production. Using cultured neonatal mouse calvariae, we found that metabolic acidosis increased medium FGF23 protein levels as well as FGF23 RNA expression at 24 h and 48 h compared with incubation in neutral pH medium. To exclude that the increased FGF23 was secondary to metabolic acidosis-induced release of bone mineral phosphate, we cultured primary calvarial osteoblasts. In these cells, metabolic acidosis increased FGF23 RNA expression at 6 h compared with incubation in neutral pH medium. Thus metabolic acidosis directly increases FGF23 mRNA and protein in mouse bone. If these results are confirmed in humans with chronic kidney disease, therapeutic interventions to mitigate acidosis, such as bicarbonate administration, may also lower levels of FGF23, decrease left ventricular hypertrophy, and perhaps even decrease mortality.osteoblasts; chronic kidney disease THE LEVEL OF THE phosphaturic hormone fibroblast growth factor 23 (FGF23) increases incrementally with declining renal function (29, 33), which results in decreased renal tubule inorganic phosphate (P i ) reabsorption (27, 33), a reduction of 1,25-dihydroxyvitamin D [1,25(OH) 2 D] (27, 33), and subsequent reduced intestinal P i absorption (33). Elevated levels of FGF23 induce left ventricular hypertrophy (6) and are associated with a significant increase in mortality (12).FGF23 is produced in osteocytes and osteoblasts (27); however, the mechanisms by which FGF23 is regulated are not clear. As patients progress from chronic kidney disease (CKD) stage 1 to stage 5, there is a significant incremental increase in FGF23, and patients on dialysis have the highest levels of FGF23 (29). The increase in both P i retention and serum P i during CKD may increase serum FGF23 (31). However, P i may not be a primary regulator of FGF23 since there is little correlation between serum P i and serum FGF23 in patients without CKD (26). 1,25(OH) 2 D has also been shown to directly increase FGF23 production and has been suggested as a "counterregulatory" hormone (24). However, in CKD, where levels of 1,25(OH) 2 D are low (23), 1,25(OH) 2 D is unlikely to be the proximate stimulus for the elevated FGF23 serum levels. Parathyroid hormone (PTH), which is elevated in patients with CKD with secondary hyperparathyroidism (23), stimulates FGF23 expression in osteoblasts (21). However, a large scale study in humans with CKD suggests that levels of FGF23 increase ...

Acid–Base Balance and Bone Health

“…We have demonstrated in mouse calvarial cultures as well as cultured mouse osteoblasts, metabolic acidosis directly increases FGF23 RNA and protein levels [131]. As this stimulation was observed in isolated cells (Fig.…”

Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism

“…19 Because oral sodium bicarbonate supplementation slows the rate of decline of renal function in patients with CKD and low plasma bicarbonate concentrations, 20 the effect of this co-therapy on the development of secondary hyperparathyroidism and vascular calcification might be considered for investigation. Of note, acidosis also increases fibroblast growth factor-23 expression in osteoblasts, raising the question of whether treating acidosis in CKD may lower fibroblast growth factor 23 21 and, indeed, PTH secretion.…”

Association of Serum Bicarbonate with Bone Fractures in Hemodialysis Patients: The Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D)

“…Acidosis also increases osteoclast resorptive activity, and reduces the deposition of alkaline mineral in bone by osteoblasts [28]. Acidosis directly increases fibroblast growth factor 23 mRNA and protein in cultured primary calvarial mouse osteoblasts [29]. In addition, metabolic acidosis is associated with the development of osteoporosis in nephrectomized CKD patients [30].…”