Osteocytic FGF23 and Its Kidney Function

Abstract

Osteocytes, which represent up to 95% of adult skeletal cells, are deeply embedded in bone. These cells exhibit important interactive abilities with other bone cells such as osteoblasts and osteoclasts to control skeletal formation and resorption. Beyond this local role, osteocytes can also influence the function of distant organs due to the presence of their sophisticated lacunocanalicular system, which connects osteocyte dendrites directly to the vasculature. Through these networks, osteocytes sense changes in circulating metabolites and respond by producing endocrine factors to control homeostasis. One critical function of osteocytes is to respond to increased blood phosphate and 1,25(OH) 2 vitamin D (1,25D) by producing fibroblast growth factor-23 (FGF23). FGF23 acts on the kidneys through partner fibroblast growth factor receptors (FGFRs) and the co-receptor Klotho to promote phosphaturia via a downregulation of phosphate transporters, as well as the control of vitamin D metabolizing enzymes to reduce blood 1,25D. In the first part of this review, we will explore the signals involved in the positive and negative regulation of FGF23 in osteocytes. In the second portion, we will bridge bone responses with the review of current knowledge on FGF23 endocrine functions in the kidneys.

Osteoporosis, an Inevitable Circumstance of Chronic Kidney Disease: A Systematic Review

“…Fibroblast growth factor and klotho: FGF is a polypeptide growth factor [27,28] and a phosphotrophic hormone produced by osteoblasts and osteocytes [28][29][30]. Its biosynthesis is positively regulated by high plasma phosphate and PTH.…”

“…Klotho is a pleiotropic protein involved in the inhibition of fibrosis, cellular aging, and apoptosis [27,30]. FGF-23, along with klotho, plays a vital role in mineral and hormone homeostasis, bone health, and mineralization [29]. In the kidney, the interaction between FGF-23 and FGFR1/klotho complex results in decreased phosphate reabsorption by internalization and degradation of the sodium-phosphate cotransporter.…”

Effect of different phosphate binders on fibroblast growth factor 23 levels in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials

“…In the kidney, physiological function of intact FGF23 is mediated by binding to the complex of fibroblast growth factor receptor (FGFR) and its specific coreceptor klotho (50). Intact FGF23 forms FGF23-FGFR-Klotho complex with FGFR and Klotho, which can inhibit expression levels of sodium-dependent phosphate transport protein 2A and sodium-dependent phosphate transport protein 2C at proximal renal tubules, thereby promote renal phosphate excretion (51)(52)(53). Furthermore, FGF23-FGFR-Klotho complex reduces serum 1,25-dihydroxyvitamin D3 levels by down-regulating renal expression of cytochrome P450 family 27 subfamily B member 1 encoding 1α-hydroxylase, which inhibits the conversion of prohormone 25-hydroxyvitamin D3 into its active form, as well as by up-regulating cytochrome P450 family 24 subfamily A member 1, which encodes catabolic 24-hydroxylase (54).…”

Crosstalk of fibroblast growth factor 23 and anemia‑related factors during the development and progression of CKD (Review)

“…HIFs are heterodimers composed of an α subunit and β subunit; HIF-α is oxygen-sensitive and stabilized due to decreased PHD-dependent hydroxylation during hypoxia (74)(75)(76). HIF-PHI stabilizes HIFs by stimulating hypoxia, thereby activating HIF signaling, inducing the transcription of endogenous EPO (77), promoting iron uptake and availability (78), and further influencing FGF23 expression (8,79,80). The HIF-PH inhibitor, roxadustat, has been used as an oral drug for the treatment of anemia (81).…”

“…The HIF-PH inhibitor, roxadustat, has been used as an oral drug for the treatment of anemia (81). This drug increases FGF23 production, suggesting that HIF-PHI may affect FGF23 expression and cleavage by inducing the transcription of endogenous EPO (80). Generally, FGF23 produced by osteocytes is affected by the level of phosphate, parathyroid hormone and 1,25(OH)2D (82).…”