"Phosphatonins" and the regulation of phosphorus homeostasis
ABSTRACT Phosphate ions are critical for normal bone mineralization, and phosphate plays a vital role in a number of other biological processes such as signal transduction, nucleotide metabolism, and enzyme regulation. The study of rare disorders associated with renal phosphate wasting has resulted in the discovery of a number of proteins [fibroblast growth factor 23 (FGF-23), secreted frizzled related protein 4 (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF 7 (FGF-7)] that decrease renal sodium-dependent phosphate transport in vivo and in vitro. The "phosphatonins," FGF-23 and sFRP-4, also inhibit the synthesis of 1alpha,25-dihydroxyvitamin D, leading to decreased intestinal phosphate absorption and further reduction in phosphate retention by the organism. In this review, we discuss the biological properties of these proteins, alterations in their concentrations in various clinical disorders, and their possible physiological role.
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- "At the end, the combination of renal phosphate wasting and calcitriol deficiency leads to osteomalacia, generalized disturbances in skeletal mineralization and thus to an increased fracture risk in patients with TIO . This is caused by factors secreted by the tumors, so-called phosphatonins . The most commonly found and best-characterized phosphatonin in TIO is FGF23  . "
ABSTRACT: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia and low calcitriol levels as well as clinical symptoms like diffuse bone and muscle pain, fatigue fractures or increased fracture risk. Conventional imaging methods, however, often fail to detect the small tumors. Lately, tumor localization clearly improved by somatostatin-receptor (SSTR) imaging, such as octreotide scintigraphy or octreotide SPECT/CT. However, recent studies revealed that still a large number of tumors remained undetected by octreotide imaging. Hence, studies focused on different SSTR imaging methods such as 68Ga DOTA-NOC, 68Ga DOTA-TOC and 68Ga DOTA-TATE PET/CT with promising first results. Studies comparing different SSTR imaging methods for tumor localization in TIO are rare and thus little is known about diagnostic alternatives once a particular method failed to detect a tumor in patients with TIO.Bone 04/2014; 64. DOI:10.1016/j.bone.2014.04.016 · 4.46 Impact Factor
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- "Recent reviews of the current understanding of these cellular signaling pathways are provided by Prié et al. (2009), Kuro-o (2010), and Ramon et al. (2010). In a review on the regulation of P homeostasis, Berndt et al. (2005) used the term phosphatonins to describe several factors thought to be involved in regulation of P. At that time, only limited information was available to define functional roles of FGF23. Initial studies of FGF23, other FGF proteins, and related receptors were based on studies of rare disorders involving renal P wasting. "
ABSTRACT: Systemic factors that ultimately affect skeletal growth involve interrelationships among Ca, parathyroid hormone (PTH), and conversion of 25-OH vitamin D(3) to the active hormone, 1α,25-(OH)(2)D(3). These interrelationships, with a focus on mechanisms that affect Ca homeostasis, are referred to as the Ca, PTH, and vitamin D axis. Relatively little research has focused on these interrelationships and P homeostasis. In the past decade, discovery of a previously unrecognized hormone involved in a pathway for P homeostasis offers opportunities to improve P efficiency without compromising skeletal growth and animal well-being. The objective of this review was to summarize pivotal research discoveries that led to the current understanding of the roles of fibroblast growth factor 23 (FGF23) in P homeostasis that are independent from the well-described pathways involved with Ca homeostasis. The novel pathways are referred to as the FGF23, P, and vitamin D axis. The peptide, FGF23, directly affects P homeostasis via action on renal target tissues to regulate Na-P transport proteins and renal 25(OH)D(3)-1α hydroxylase activity. Identification of bone as the primary site for FGF23 production ascribes an endocrine gland function to bone. Within 9 h after a single injection of recombinant FGF23, mice displayed hypophosphatemia and urinary P wasting. In contrast, FGF23 knockout mice displayed hyperphosphatemia and renal P conservation. These responses were independent of PTH. Applications of the FGF23, P, and vitamin D axis in dietary strategies for animal agriculture need to be explored. Development of dietary inputs to balance both Ca and P homeostasis are needed to improve skeletal growth and nutrient efficiency.Journal of Animal Science 11/2010; 89(7):1957-64. DOI:10.2527/jas.2010-3411 · 1.92 Impact Factor
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- "The regulation of phosphate in the body is maintained by intestinal absorption, renal excretion, and bone remodeling under the control of parathyroid hormone (PTH), 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], and 24,25-dihydroxyvitamin D 3 [24,25(OH) 2 D 3 ]  . Phosphate is required for normal cellular functions and physiological processes such as energy metabolism, nucleic acid synthesis, bone mineralization, and cell signaling . The effects of 1,25(OH) 2 D 3 are mediated through slower transcriptional effects over a period of hours initiated by the nuclear vitamin D receptor (VDR), and possibly the 1,25D 3 -MARRS receptor [4,5] and by rapid responses occurring within seconds to minutes , mediated through membrane-initiated signal transduction pathways . "
ABSTRACT: We undertook studies to determine which isotype(s) of protein kinase C (PKC) is/are activated by ligand binding to the 1,25D(3)-MARRS receptor (ERp57/PDIA3) and subsequent stimulation of phosphate uptake. Isolated intestinal epithelial cells from vitamin D-replete chicks were exposed to 1,25(OH)(2)D(3) for 1, 3, or 5min, thoroughly chilled, homogenized, and P(2) fractions (20,000xg post-nuclear pellet) prepared. Western analyses with anti-pan PKC revealed steroid-stimulated redistribution to P(2) membranes 1min after hormone. Using this time point, cells were treated with vehicle, 130-, 300- or 650-pM hormone. Western blots with anti-PKCalpha exhibited redistribution to membranes in a biphasic dose-response curve: slightly stimulated at the lowest dose, maximal at 300pM 1,25(OH)(2)D(3), and equivalent to control levels at the highest dose, paralleling hormone-mediated phosphate uptake. Westerns with anti PKCbeta also revealed hormone-mediated differences, while those with anti PKCgamma did not. RNAi studies were then performed with siRNA against PKCalpha or PKCbeta. Untransfected cells treated with hormone for 7min exhibited enhanced (32)P uptake relative to vehicle controls. Cells transfected with either active siRNA revealed decreased (32)P uptake in both controls (relative to untransfected controls), and hormone treated cells. However, control and transfected cells treated with hormone had equivalent levels of uptake. Western blot analyses confirmed decreased immunoreactivity in transfected cells. Chemical PKCalpha (safingol) and PKCbeta ([3-(1-(3-Imidazol-1-ylpropyl)-1H-indol-3-yl)-4-anilino-1H-pyrrole-2,5-dione] blockers also confirmed the results from siRNA and demonstrated decreased (32)P uptake in cells treated with 1,25(OH)(2)D(3) plus blockers in comparison with cells treated with 1,25(OH)(2)D(3) alone. Thus, PKCalpha and PKCbeta are both involved in steroid-stimulated phosphate uptake.Steroids 04/2010; 75(4-5):307-13. DOI:10.1016/j.steroids.2010.01.004 · 2.72 Impact Factor