Abstract
Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, mainly produced by osteoblasts and osteocytes in response to increased extracellular phosphate and circulating vitamin D hormone. Endocrine FGF23 signaling requires co-expression of the ubiquitously expressed FGF receptor 1 (FGFR1) and the co-receptor α-Klotho (Klotho). In proximal renal tubules, FGF23 suppresses the membrane expression of the sodium–phosphate cotransporters Npt2a and Npt2c which mediate urinary reabsorption of filtered phosphate. In addition, FGF23 suppresses proximal tubular expression of 1α-hydroxylase, the key enzyme responsible for vitamin D hormone production. In distal renal tubules, FGF23 signaling activates with-no-lysine kinase 4, leading to increased renal tubular reabsorption of calcium and sodium. Therefore, FGF23 is not only a phosphaturic but also a calcium- and sodium-conserving hormone, a finding that may have important implications for the pathophysiology of chronic kidney disease. Besides these endocrine, Klotho-dependent functions of FGF23, FGF23 is also an auto-/paracrine suppressor of tissue-nonspecific alkaline phosphatase transcription via Klotho-independent FGFR3 signaling, leading to local inhibition of mineralization through accumulation of pyrophosphate. In addition, FGF23 may target the heart via an FGFR4-mediated Klotho-independent signaling cascade. Taken together, there is emerging evidence that FGF23 is a pleiotropic hormone, linking bone with several other organ systems.
Highlights
Intact fibroblast growth factor-23 (FGF23) circulating in the bloodstream is a 32-kDa glycoprotein consisting of 227 amino acids
FGF23 was discovered as a novel member of the FGF family in the year 2000, when mutations putatively interfering with cleavage of the protein were identified as the cause of autosomal dominant hypophosphatemic rickets (ADHRs), an inherited renal phosphate-wasting disease (The ADHR Consortium 2000)
We recently showed that this mechanism contributes to impaired mineralization in diseases characterized by increased osteocytic production of FGF23: increased osteocytic FGF23 secretion in Hyp mice suppressed tissue-nonspecific alkaline phosphatase (Tnap) activity in osteocytes and increased pyrophosphate concentrations in bone, which could be rescued by bone-specific deletion of Fgf23 (Murali, Andrukhova, et al 2016)
Summary
Intact fibroblast growth factor-23 (FGF23) circulating in the bloodstream is a 32-kDa glycoprotein consisting of 227 amino acids. FGF23 was discovered as a novel member of the FGF family in the year 2000, when mutations putatively interfering with cleavage of the protein were identified as the cause of autosomal dominant hypophosphatemic rickets (ADHRs), an inherited renal phosphate-wasting disease (The ADHR Consortium 2000). In subjects with normal kidney function, increased blood concentrations of intact FGF23 lead to renal phosphate wasting and subsequently impaired bone mineralization. Increased serum concentrations of intact FGF23 are a hallmark of renal phosphate-wasting diseases such as ADHR, X-linked hypophosphatemia (XLH), tumor-induced osteomalacia, or autosomal recessive hypophosphatemic rickets 1 (Martin, David, and Quarles 2012). Another elimination pathway for FGF23 is ultrafiltration in the kidney. It is likely that reductions in glomerular filtration rate per se lead to concomitant increases in circulating FGF23 concentration
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