Fibroblast growth factor 23 and α-Klotho co-dependent and independent functions

Abstract

Purpose of review: The current review examines what is known about the FGF-23/α-Klotho co-dependent and independent pathophysiological effects, and whether FGF-23 and/or α-Klotho are potential therapeutic targets.

Recent findings: FGF-23 is a hormone derived mainly from bone, and α-Klotho is a transmembrane protein. Together they form a trimeric signaling complex with FGFRs in target tissues to mediate the physiological functions of FGF-23. Local and systemic factors control FGF-23 release from osteoblast/osteocytes in bone, and circulating FGF-23 activates FGFR/α-Klotho complexes in kidney proximal and distal renal tubules to regulate renal phosphate excretion, 1,25 (OH)2D metabolism, sodium and calcium reabsorption, and ACE2 and α-Klotho expression. The resulting bone-renal-cardiac-immune networks provide a new understanding of bone and mineral homeostasis, as well as identify other biological effects FGF-23. Direct FGF-23 activation of FGFRs in the absence of α-Klotho is proposed to mediate cardiotoxic and adverse innate immune effects of excess FGF-23, particularly in chronic kidney disease, but this FGF-23, α-Klotho-independent signaling is controversial. In addition, circulating soluble Klotho (sKl) released from the distal tubule by ectodomain shedding is proposed to have beneficial health effects independent of FGF-23.

Summary: Separation of FGF-23 and α-Klotho independent functions has been difficult in mammalian systems and understanding FGF-23/α-Klotho co-dependent and independent effects are incomplete. Antagonism of FGF-23 is important in treatment of hypophosphatemic disorders caused by excess FGF-23, but its role in chronic kidney disease is uncertain. Administration of recombinant sKl is an unproven therapeutic strategy that theoretically could improve the healt span and lifespan of patients with α-Klotho deficiency.

Figure 1.. Venn diagram of FGF-23 and α-Kl signaling mechanisms and pathophysiological functions.

FGF-23/α-Kl co-dependent canonical signaling (middle circle), α-Kl dependent/FGF-23 independent sKL signaling (right circle), and FGF-23 dependent/ α-Kl independent non-canonical signaling (left circle).

Figure 2.. Transcriptional control of FGF-23.

A) Cell signaling pathways and B) transcription factors and cis-elements in the proximal promoter regulating FGF-23 gene transcription. C) Mouse FGF-23 gene showing proximal promoter, silencer region, transcriptional repressor CTCF and four enhancers. D) Location of the potential enhancer regions by histone modifications and CTCF binding at −38, −16, −10, and + 7kb from the TSS across the FGF-23 genetic locus.

Figure 3.. FGF-23 regulates innate immune responses.

Inflammation stimulates FGF-23 expression in bone, and ectopic expression of FGF-23 in M1 macrophages to create both systemic and paracrine signaling. a. FGF-23 blocks macrophage transition to M2 and resolution of inflammation. b. FGF-23 activates FGFR/α-Kl complexes in macrophages to stimulate TNF-α and promote inflammation. c. FGF-23 may activate FGFR2 to impair PMN recruitment. d. FGF-23 through FGFR/α-Kl in the kidney suppresses 1,25(OH)₂D, creating networks that further modulate host responses to infection.

Figure 4.. Indirect and Direct Mechanisms of FGF-23 cardiac effects.

A) Canonical mechanisms whereby FGF-23 regulates cardiovascular functions through a bone-kidney-cardiac endocrine network. LVH could be due to effects of FGF-23 to suppress ACE2 expression or stimulate distal tubular sodium reabsorption. Alternatively, FGF-23 induced LVH could be mediated by suppression of sKL release by the kidney and the effect of sKl to increase TRP6 in the heart. B) Proposed non-canonical direct effects of FGF-23 on FGFR4 in the heart.