Regulation and function of the FGF23/klotho endocrine pathways

Abstract

Calcium (Ca(2+)) and phosphate (PO(4)(3-)) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca(2+) levels by increasing Ca(2+) reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] production by the kidney, enhancing Ca(2+) and PO(4)(3-) intestinal absorption and increasing Ca(2+) and PO(4)(3-) efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)(2)D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)(2)D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO(4)(3-) handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.

FIGURE. 1

Functional evolutionary history of ancestors of the mouse Fgf gene family. [From Itoh et al. (75), with permission from John Wiley and Sons.]

FIGURE. 2

Renal and extrarenal functions of FGF23. A: hypothetical distal to proximal feedback mechanism: FGF23 activates FGFR/Klotho complexes in the renal distal tubules (DT) leading to two predominant events in the proximal convoluted tubules (PCT): the inhibition of expression of Npt2a and the inhibition of Cyp27b1. As a consequence, phosphate reabsorption and 1,25(OH)₂D production are respectively decreased. Additionally, the increase in Cyp24a1 expression contributes to lowering 1,25(OH)₂D levels due to increased catabolism of 1,25(OH)₂D. B: extrarenal targets of FGF23 are tissues that express FGFR and Klotho, including kidney, but also parathyroid gland (PTG), heart, and brain (brown arrows) or tissues that express the FGFR alone such as thymus, spleen, or bone (gray arrows), indicating possible paracrine effects of FGF23. Possible hormonal regulation loops are yet to be discovered.

FIGURE. 3

Predictive model for local regulation of Fgf23 transcription in bone. The COOH-terminal fragment of DMP1 binds to PHEX and integrins via the ASARM and the RGD motifs, respectively. A: in physiological conditions, this binding participates in maintaining low circulating FGF23 levels by inhibiting its transcription. B: absence of DMP1 or PHEX, due to inactivating mutations, leads to a pathological increase in Fgf23 transcription by stimulation of the FGFs/FGFRs pathway. Activation of the FGFs/FGRs pathway occurs when integrins are release from COOH-terminal DMP1 binding and low-molecular-weight FGFs (LMW-FGFs) are released from NH₂-terminal DMP1 binding, thus allowing the formation of a complex between LMW-FGFs/integrins/FGFR. Alternatively, internalization of intracytoplasmic FGFR and high-molecular-weight FGFs (HMW-FGFs) also lead to increased Fgf23 transcription in absence of DMP1 and PHEX.