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Unlike paracrine FGFs, such as FGF1 or FGF2, endocrine FGFs share a characteristic structure and lack the heparin-binding domain in their C-terminus which enables their secretion, circulation, and action on distant target organs ( 5, 6).įGF23 is a bone-derived hormone that lowers serum phosphate levels ( 7– 9). Members of the FGF19 subfamily, consisting of FGF19, FGF21, and FGF23, function as circulating hormones and are, therefore, termed endocrine FGFs ( 3, 4). FGFs are divided into seven subfamilies based on phylogenic analyses and overlapping structures ( 2). The family of fibroblast growth factors (FGF) consists of 22 members in humans, with a broad range of biological functions, including the regulation of embryonic development, organogenesis, and metabolism ( 1). Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might-at least partially-underlie the pleiotropic tissue-protective functions of klotho. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23’s potential role as a hormone with widespread pathologic actions.
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This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in “classic” klotho-expressing target organs. Recently, it has been shown that FGF23 can also target cell types that lack klotho. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United Statesįibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs.