Biomedical subjects

Susan C Schiavi

Publications and source records attributed to Susan C Schiavi.

6 recordsLinked to original sources

PubMed2006

FGF-23 and sFRP-4 in chronic kidney disease and post-renal transplantation.

BACKGROUND: The phosphatonins fibroblast growth factor-23 (FGF-23) and FRP-4 are inhibitors of tubular phosphate reabsorption that may play a role in the hyperphosphatemia associated with chronic kidney disease (CKD) or in the hypophosphatemia associated with renal transplants. METHODS: Plasma FGF-23, FRP-4, phosphorus and parathyroid hormone were measured in patients at all stages of CKD. Phosphate regulation of FGF-23 and secreted frizzled related protein-4 (sFRP-4) was examined in end-stage renal disease patients in the presence and absence of therapeutic phosphate binder usage. In renal transplant patients, plasma FGF-23, sFRP-4 and phosphorus concentrations were determined before and 4-5 days after transplantation. RESULTS: Plasma FGF-23 correlated with creatinine clearance (r2 = -0.584, p < 0.0001) and plasma phosphorus (r2 = 0.347, p < 0.001) in CKD patients and with plasma phosphorus (r2 = 0.448, p < 0.001) in end-stage renal disease patients. Phosphate binder withdrawal increased FGF-23 levels. In kidney transplant patients, dramatic decreases in FGF-23 (-88.8 +/- 5.4%) and phosphorus (-64 +/- 10.2%) were observed by 4-5 days post-transplantation. In patients with post-transplant hypophosphatemia, FGF-23 levels correlated inversely with plasma phosphorus (r2 = 0.661, p < 0.05). sFRP-4 levels did not change with creatinine clearance or hyperphosphatemia in CKD or end-stage renal disease patients, and no relation was noted between post-transplant sFRP-4 levels and hypophosphatemia. CONCLUSIONS: In CKD, FGF-23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels, and rapidly decreased post-transplantation suggesting FGF-23 is cleared by the kidney. Residual FGF-23 may contribute to the hypophosphatemia in post-transplant patients.

Female↗

PubMed2006

Bone talk.

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Animals↗

PubMed2004

The phosphatonin pathway: new insights in phosphate homeostasis.

Serum phosphate concentrations are maintained within a defined range by processes that regulate the intestinal absorption and renal excretion of inorganic phosphate. The hormones currently believed to influence these processes are parathyroid hormone (PTH) and the active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)2D). A new class of phosphate-regulating factors, collectively known as the phosphatonins, have been shown to be associated with the hypophosphatemic diseases, tumor-induced osteomalacia (TIO), X-linked hypophosphatemic rickets (XLH), and autosomal-dominant hypophosphatemic rickets (ADHR). These factors, which include fibroblast growth factor 23 (FGF23) and secreted frizzled-related protein 4 (FRP4), decrease extracellular fluid phosphate concentrations by directly reducing renal phosphate reabsorption and by suppressing 1alpha,25(OH)2D formation through the inhibition of 25-hydroxyvitamin D 1alpha-hydroxylase. The role of these substances under normal or pathologic conditions is not yet clear. For example, it is unknown whether any of the phosphatonins are directly responsible for the decreased concentrations of 1alpha,25(OH)2D observed in chronic and end-stage kidney disease or whether they are induced in an attempt to correct the hyperphosphatemia seen in late stages of chronic renal failure. Future experiments should clarify their physiologic and pathologic roles in phosphate metabolism.

Animals↗

PubMed2003

Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent.

Tumors associated with osteomalacia elaborate the novel factor(s), phosphatonin(s), which causes phosphaturia and hypophosphatemia by cAMP-independent pathways. We show that secreted frizzled-related protein-4 (sFRP-4), a protein highly expressed in such tumors, is a circulating phosphaturic factor that antagonizes renal Wnt-signaling. In cultured opossum renal epithelial cells, sFRP-4 specifically inhibited sodium-dependent phosphate transport. Infusions of sFRP-4 in normal rats over 2 hours specifically increased renal fractional excretion of inorganic phosphate (FEPi) from 14% +/- 2% to 34% +/- 5% (mean +/- SEM, P < 0.01). Urinary cAMP and calcium excretion were unchanged. In thyro-parathyroidectomized rats, sFRP-4 increased FEPi from 0.7% +/- 0.2% to 3.8% +/- 1.2% (P < 0.05), demonstrating that sFRP-4 inhibits renal inorganic phosphate reabsorption by PTH-independent mechanisms. Administration of sFRP-4 to intact rats over 8 hours increased FEPi, decreased serum phosphate (1.95 +/- 0.1 to 1.53 +/- 0.09 mmol/l, P < 0.05) but did not alter serum 1alpha, 25-dihydroxyvitamin D, renal 25-hydroxyvitamin D 1alpha-hydroxylase cytochrome P450, and sodium-phosphate cotransporter mRNA concentrations. Infusion of sFRP-4 antagonizes Wnt action as demonstrated by reduced renal beta-catenin and increased phosphorylated beta-catenin concentrations. The sFRP-4 is detectable in normal human serum and in the serum of a patient with tumor-induced osteomalacia. Thus, sFRP-4 displays phosphatonin-like properties, because it is a circulating protein that promotes phosphaturia and hypophosphatemia and blunts compensatory increases in 1alpha, 25-dihydroxyvitamin D.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed2002

Phosphatonins: a new class of phosphate-regulating proteins.

PURPOSE OF REVIEW: There is an intimate relationship between phosphate and calcium homeostasis throughout the animal kingdom. One traditional assumption is that all phosphate-regulating hormones are primarily calcium-regulating hormones. Although the notion of a circulating substance dedicated to phosphate homeostasis has existed for more than a decade, it is not until recently that these hormones have been identified. The molecular characterization of these substances will prove to be critical for understanding phosphate physiology and clinical disorders of phosphate metabolism. RECENT FINDINGS: This review will focus primarily on the first two proteins recently shown to have phosphatonin properties. Using three human diseases as models and a combination of positional cloning and differential gene expression, fibroblast growth factor 23 and frizzled-related protein 4 were shown to be associated with one or more of these diseases. Although both of these substances have phosphaturic action, their biological effects are likely to extend beyond epithelial phosphate transport. SUMMARY: The phosphatonins are a growing family of substances that may act on multiple organs in autocrine, paracrine, and endocrine modes to regulate phosphate metabolism. As this list expands, the need for a more rigid definition of the term phosphatonin becomes evident. The identification and characterization of these phosphate-regulatory compounds will provide a clearer understanding of how individual phosphatonins regulate phosphate in normal and disease physiology.

Animals↗

PubMed2002

Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism.

Oncogenic osteomalacia (OOM) is associated with primitive mesenchymal tumors that secrete phosphaturic factors resulting in low serum concentrations of phosphate and calcitriol, phosphaturia, and defective bone mineralization. To identify overexpressed genes in these tumors, we compared gene expression profiles of tumors resected from patients with OOM and histologically similar control tumors using serial analysis of gene expression (SAGE). Three hundred and sixty-four genes were expressed at least twofold greater in OOM tumors compared with control tumors. A subset of 67 highly expressed genes underwent validation with an extended set of OOM and control tumors using array analysis or reverse-transcription polymerase chain reaction (RT-PCR). Ten of these validated genes were consistently overexpressed in all OOM tumors relative to control tumors. Strikingly, genes with roles in bone matrix formation, mineral ion transport, and bone mineralization were highly expressed in the OOM tumors.

Base Sequence↗