Elevated fibroblast growth factor‐23 in hypophosphatemic linear nevus sebaceous syndrome

Hoffman, William H.; Jueppner, Harald; DeYoung, Barry R.; O’Dorisio, M. Sue; Given, Keena S.

doi:10.1002/ajmg.a.30599

Cited by 84 publications

(60 citation statements)

References 42 publications

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“…A subset of these patients have ipsilateral focal bone disease associated with hypophosphatemic rickets, elevated circulating FGF23 levels, and aberrant 1,25(OH) 2 D levels, similar to other syndromes that are caused by elevated FGF23. Treatment with the somatostatin agonist octreotide and excision of the nevus have been reported to normalize FGF23 (63)(64)(65).…”

Section: Sporadic/acquired Disordersmentioning

confidence: 99%

How Fibroblast Growth Factor 23 Works

Liu

Quarles

2007

Journal of the American Society of Nephrology

366

341

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There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (FGF23). Disorders that are caused by high circulating levels of FGF23 are characterized by hypophosphatemia, decreased production of 1,25-dihydroxyvitamin D, and rickets/osteomalacia. On the other end of the spectrum are disorders that are caused by low circulating levels of FGF23, which are characterized by hyperphosphatemia, elevated production of 1 Fibroblast Growth Factor 23 Gene and Protein StructureThe fibroblast growth factor (FGF) family consists of 22 members with varied functions (2). FGF23 is an approximately 32-kD (251 amino acids) protein with an N-terminal region that contains the FGF homology domain and a novel 71-amino acid C-terminus that was originally discovered by homology-based PCR screening of a mouse embryonic cDNA library (3). The FGF23 gene is located on Chr 12p13 and is phylogenetically grouped with FGF19 and 21 gene products (2,3), with which it has approximately 24% and approximately 22% amino acid identities, respectively. FGF23 principally acts as a phosphaturic factor and suppressor of 1␣-hydroxylase activity in the kidney (4,5), making it functionally distinct from other members of this family. Tissue Expression and Function: Evidence for a Bone-Kidney AxisFGF23 is predominately expressed in osteocytes in bone (6,7), but it is also expressed in pericyte-like cells that surround the venous sinuses in the bone marrow, in the ventrolateral thalamic nucleus, and in thymus and lymph nodes (Figure 1). The relative contribution of these sites to circulating FGF23 levels is not known, but the high levels of expression in the osteocyte and that osteocytes are the most abundant cell in bone suggest that the serum levels of FGF23 are derived mainly from bone. In addition, the production of FGF23 by osteocytes, cells that are central to the regulation of osteoblast function and mineralization, likely has functional significance (8). In this regard, osteocytes secrete sclerostin, an inhibitor of bone formation and the phosphaturic factor FGF23, as well as other gene products, such as phosphate-regulating endopeptidase homolog, X-linked (Phex), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE), that regulate bone mineralization and FGF23 expression. Phex is a type I cell surface zinc metalloprotease that is involved in the regulation of FGF23 levels and is mutated in X-linked hypophosphatemic rickets (9). Both DMP1 and MEPE are glycophosphoproteins that belong to the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of proteins. MEPE and DMP1 are predominately expressed in bones and/or teeth, where they respectively inhibit and induce mineralization of extracellular matrix (10). These associations suggest that osteocytes coordinate osteoblast-mediated bone formation with renal regulation of systemic phosphate homeostasis through the regu...

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Section: Sporadic/acquired Disordersmentioning

confidence: 99%

How Fibroblast Growth Factor 23 Works

Liu

Quarles

2007

Journal of the American Society of Nephrology

366

341

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“…Its physiological importance is exemplified by numerous activating and inactivating mutations in the human FGF23 gene, causing two clinical disorders of disturbed Pi homeostasis: autosomal dominant hypophosphatemic rickets (ADHR, OMIM#193100; ADHR-Consortium 2000) and hyperphosphatemic familial tumoral calcinosis (HFTC, OMIM#211900; Benet-Pages et al 2005, Larsson et al 2005. Elevated FGF23 levels are also associated with several other disorders of hypophosphatemia or dysfunctional regulation of vitamin D, such as autosomal recessive hypophosphatemic rickets (ARHR; Feng et al 2006, Lorenz-Depiereux et al 2006, X-linked hypophosphatemic rickets (XLH; Liu et al 2003, Riminucci et al 2003, tumor-induced osteomalacia (TIO; Shimada et al 2001, White et al 2001b, fibrous dysplasia (FD; Riminucci et al 2003), and linear nevus sebaceous syndrome (LNSS; Hoffman et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells

Krajisnik¹,

Björklund

Marsell

et al. 2007

Journal of Endocrinology

428

268

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Fibroblast growth factor-23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate (Pi) as well as 1,25-dihydroxyvitamin D 3 . Recent studies also suggest a correlation between serum levels of FGF23 and parathyroid hormone (PTH) in patients with chronic kidney disease. It is, however, unknown whether FGF23 directly modulates PTH expression, or whether the correlation is secondary to abnormalities in Pi and vitamin D metabolism. The objective of the current study was therefore to elucidate possible direct effects of FGF23 on bovine parathyroid cells in vitro. Treatment of parathyroid cells with a stabilized form of recombinant FGF23 (FGF23(R176Q)) induced a rise in early response gene-1 mRNA transcripts, a marker of FGF23 signaling. FGF23(R176Q) potently and dose-dependently decreased the PTH mRNA level within 12 h. In agreement, FGF23(R176Q) also decreased PTH secretion into conditioned media. In contrast, FGF23(R176Q) dose-dependently increased 1a-hydroxylase expression within 3 h. FGF23 (R176Q) did not affect cell viability nor induce apoptosis, whereas a small but significant increase in cell proliferation was found. We conclude that FGF23 is a negative regulator of PTH mRNA expression and secretion in vitro. Our data suggest that FGF23 may be a physiologically relevant regulator of PTH. This defines a novel function of FGF23 in addition to the previously established roles in controlling vitamin D and Pi metabolism.

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“…The pathogenic mechanism involved in the onset of hypophosphataemic rickets in ENS is not fully clarified. It has been proposed that FGF23 is the putative phosphatonin, based on demonstration of its elevated blood levels in a patient with LNSS (56). Subsequent studies also found the same result (119)(120).…”

Section: Linear Nevus Sebaceous Syndrome (Lnss)mentioning

confidence: 85%

“…Genetic disorders include Xlinked dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets (35, 50-51), autosomal dominant hypophosphatemic rickets (1), hypophosphatemic rickets associated with McCune-Albright syndrome (52-54) and Linear sebaceous nevus syndrome (55)(56)(57). Acquired disorders include tumor induced osteomalacia.…”

Section: High Fgf23 and Disorders With Abnormal Phosphate Metabolismmentioning

confidence: 99%

FGF23 and Phosphate Wasting Disorders

2013

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A decade ago, only two hormones, parathyroid hormone and 1,25(OH)2D, were widely recognized to directly affect phosphate homeostasis. Since the discovery of fibroblast growth factor 23 (FGF23) in 2000 (1), our understanding of the mechanisms of phosphate homeostasis and of bone mineralization has grown exponentially. FGF23 is the link between intestine, bone, and kidney together in phosphate regulation. However, we still do not know the complex mechanism of phosphate homeostasis and bone mineralization. The physiological role of FGF23 is to regulate serum phosphate. Secreted mainly by osteocytes and osteoblasts in the skeleton (2-3), it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23 or hypo-FGF23. Hyper-FGF23 is related to hypophosphatemia, while hypo-FGF23 is related to hyperphosphatemia. Both hyper-FGF23 and hypo-FGF23 are detrimentalto humans. In this review, we will discuss the pathophysiology of FGF23 and hyper-FGF23 related renal phosphate wasting disorders (4 IntroductionAccording to pathogenesis, ricketsis classified into calicopenic rickets, phosphopenicrickets, and a miscellaneous group associated with direct inhibitors of mineralization ( 5). In general, most instances of nutritional rickets are calicopenic, whereas heritable causes are usually phosphopenic. In this review we focus on hypophosphatemic rickets or osteomalacia. The causes of hypophosphatemia are various, of whichthe most prominent one is decreased reabsorption of phosphate in the proximal tubule.Although renal tubular disease can result in excessive renal phosphate wasting, in most hypophosphatemic disordersno abnormalities are found in the proximal tubule (6-7). It is speculated that an unknown factor is responsible for this phenomenon. The discovery of fibroblast growth factor 23 (FGF23), a member of the Phosphate homeostasisPhosphate comprises about 1% of total body weight. About 85% of total body phosphate resides in the bone, 14% in the cells, and only 1% in the serum and extracellular fluids. Maintenance of serum phosphate within its normal range allows for optimal mineralization of bone without deposition in vascular and other soft tissues. Serum phosphate concentration is determined Xianglan Huang et al. www.boneresearch.org | Bone Research 121by the balance among intestinal absorption of phosphate from the diet, its storage in bone, and its excretion in the urine. The proximal tubule is responsible for the reabsorption of phosphate filtered at the glomerulus and is the primary regulator of phosphate balance in the body. Transportation in the proximal tubule is driven primarily by sodium-potassium ATPase, which is located in the baso-lateral membrane of the cell (8-11). Under normal conditions, about 85% of the filtered phosphate is reabsorbed via the sodium-phosphate co-transporter (NaPi2a and NaPi2c) in the proximal tubule (9, 11). Parathyroid hormone (PTH) is one of the most potent horm...

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Elevated fibroblast growth factor‐23 in hypophosphatemic linear nevus sebaceous syndrome

Cited by 84 publications

References 42 publications

How Fibroblast Growth Factor 23 Works

How Fibroblast Growth Factor 23 Works

Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells

FGF23 and Phosphate Wasting Disorders

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