Fibroblast growth factor-23 (FGF23) is a hormone originating from osteocytes with suppressive actions on renal phosphate reabsorption and vitamin D synthesis. We recently identified FGF23 as a calcium-conserving hormone, regulating the membrane transport of the epithelial calcium channel TRPV5 in distal renal tubules. Here, we analyzed the long term sequelae of Fgf23 deficiency and renal calcium wasting on bone and mineral metabolism in 9-month-old mice lacking both Fgf23 and a functioning vitamin D receptor (VDR). To prevent secondary hyperparathyroidism (sHPT) in VDR deficient mice, the mice were kept on a so-called rescue diet enriched with calcium, phosphate, and lactose. VDR mutants were normocalcemic and normophosphatemic, and had normal tibial bone mineral density (BMD), but slightly increased serum intact PTH. Relative to VDR mutants, compound mutants had unchanged serum calcium, but were characterized by hyperphosphatemia and very high serum PTH. sHPT in compound mutants was associated with only moderate cortical bone loss at the tibial shaft. Despite ~13-fold higher serum PTH levels in compound mutants, urinary excretion of phosphate, calcium, and deoxypyridinoline remained unchanged relative to VDR mutants. The increase in plasma cAMP 10 min after injection of hPTH(134) was similar in WT, VDR and Fgf23/VDR mutant mice. However, a 5-day infusion of hPTH(134) via osmotic minipumps resulted in reduced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in bone and kidney protein homogenates of Fgf23/VDR compound mutants, relative to VDR and WT controls. Similarly, the PTH-mediated ERK1/2 phosphorylation was blunted in primary osteoblasts isolated from Fgf23/VDR mutant mice, but was completely restored by concomitant treatment with recombinant FGF23. Collectively, our data indicate that the phosphaturic, calcium-conserving, and bone resorption-stimulating actions of PTH are blunted by Fgf23 deficiency. Hence, FGF23 may be an important modulator of PTH signaling in bone and kidney.
17 May 2014 - 20 May 2014