Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism

Abstract

The discovery of fibroblast growth factor 23 (FGF-23) has expanded our understanding of phosphate and vitamin D homeostasis and provided new insights into the pathogenesis of hereditary hypophosphatemic and hyperphosphatemic disorders, as well as acquired disorders of phosphate metabolism, such as chronic kidney disease. FGF-23 is secreted by osteoblasts and osteocytes in bone and principally targets the kidney to regulate the reabsorption of phosphate, the production and catabolism of 1,25-dihydroxyvitamin D and the expression of α-Klotho, an anti-ageing hormone. Secreted FGF-23 plays a central role in complex endocrine networks involving local bone-derived factors that regulate mineralization of extracellular matrix and systemic hormones involved in mineral metabolism. Inactivating mutations of PHEX, DMP1 and ENPP1, which cause hereditary hypophosphatemic disorders and primary defects in bone mineralization, stimulate FGF23 gene transcription in osteoblasts and osteocytes, at least in part, through canonical and intracrine FGF receptor pathways. These FGF-23 regulatory pathways may enable systemic phosphate and vitamin D homeostasis to be coordinated with bone mineralization. FGF-23 also functions as a counter-regulatory hormone for 1,25-dihydroxyvitamin D in a bone-kidney endocrine loop. FGF-23, through regulation of additional genes in the kidney and extrarenal tissues, probably has broader physiological functions beyond regulation of mineral metabolism that account for the association between FGF-23 and increased mortality and morbidity in chronic kidney disease.

Figure 1

A speculative model of FGF23 gene transcriptional regulation. Four activating mutations or pathways (involving FGFR-1, Gα_s encoded by GNAS, PTH/PTHr receptor and HMW-FGF-2) and four inactivating mutations (involving PHEX, DMP-1, E-NPP1 and ANK-1) are associated with increased FGF-23 expression in bone. Local bone-derived factors that are linked to mineralization are shown on the right-hand side. ANK-1 and E-NPP1 regulate the transport and biosynthesis of pyrophosphate, and TNAP regulates the conversion of pyrophosphate to phosphate in the extracellular matrix mineralization process, whereas both PHEX and DMP-1 regulate bone mineralization through mechanisms that remain to be fully elucidated. Evidence exists in osteoblasts derived from the Hyp mouse model that defective mineralization is linked to the activation of FGFR-1 as well as HMW-FGF-2 integrative nuclear signaling pathways. The left-hand side of the figure shows systemic factors involved in FGF-23 regulation. 1,25-dihydroxyvitamin D is an important regulator of FGF-23 expression, acting through the VDR and VDRE. PTH can also stimulate FGF-23 through a sclerostin-dependent mechanism involving the Wnt–β-catenin pathway, or through stimulation of GNAS and cAMP-dependent signaling pathways, as well as indirectly through stimulation of 1,25-dihydroxyvitamin D. Intrinsic and systemic factors are integrated at the levels of cis-acting elements in the proximal FGF23 promoter that remain to be elucidated. A question mark (?) indicates areas of uncertainty. Abbreviations: Hyp, mouse model of X-linked hypophosphatemic rickets; PO₄, phosphate; PPi, pyrophosphate; TK, tyrosine kinase.