FGF23 and Vitamin D Metabolism

Apart from its phosphaturic action, the bone-derived hormone fibroblast growth factor-23 (FGF23) is also an essential regulator of vitamin D metabolism. The main target organ of FGF23 is the kidney, where FGF23 suppresses transcription of the key enzyme in vitamin D hormone (1,25(OH)(2)D) activation, 1 alpha-hydroxylase, and activates transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase, in proximal renal tubules. The circulating concentration of 1,25(OH)(2)D is a positive regulator of FGF23 secretion in bone, forming a feedback loop between kidney and bone. The importance of FGF23 as regulator of vitamin D metabolism is underscored by the fact that in the absence of FGF23 signaling, the tight control of renal 1 alpha-hydroxylase fails, resulting in overproduction of 1,25(OH)(2)D in mice and men. During recent years, big strides have been made toward a more complete understanding of the mechanisms underlying the FGF23-mediated regulation of vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. Importantly, the intracellular signaling cascades downstream of FGF receptors regulating transcription of 1 alpha-hydroxylase and 24-hydroxylase in proximal renal tubules still remain unresolved. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the regulation of vitamin D metabolism by FGF23, and to discuss the role of these mechanisms in physiology and pathophysiology. (c) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Automated summary

FGF23 acts as a crucial regulator of vitamin D metabolism, primarily in the kidney, by inhibiting and activating key enzymes involved in the activation and degradation of vitamin D. 1,25(OH)(2)D serves as a positive regulator of FGF23 secretion, establishing a feedback loop between the kidney and bone. While there has been progress in understanding the genomic mechanisms of FGF23-mediated regulation of vitamin D metabolism, unresolved issues still exist regarding intracellular signaling cascades.