Identification of a Novel Fibroblast Growth Factor, FGF-23, Preferentially Expressed in the Ventrolateral Thalamic Nucleus of the Brain

Yamashita, Tetsuo; Yoshioka, Masazumi; Itoh, Nobuyuki

doi:10.1006/bbrc.2000.3696

Cited by 505 publications

(351 citation statements)

References 22 publications

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“…FGF23 activating mutations are responsible for the changes in phosphate, vitamin D metabolism and mineralization in ADHR [4,82,97,98] and overexpression of wild-type FGF23 in some but not all OHO tumors is directly or indirectly responsible for the changes in some tumor-induced osteomalacias [15,81,97,99]. Also, a number of groups have reported lack of FGF23 expression in bone/osteoblasts [3,27,29,41,98,104] and others using more sensitive techniques have detected low levels of FGF23 mRNA in bone tissue but not in normal murine osteoblasts [40]. This suggests a complex pathway involving extra-osteoblastic phosphatonins (EO-PTN) and osteoblastic phosphatonins (OB-PTN) in Hyp.…”

Section: Discussionmentioning

confidence: 99%

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Rowe

Kumagai²,

Gutiérrez³

et al. 2004

Bone

247

277

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Matrix extracellular phosphoglycoprotein (MEPE) is expressed exclusively in osteoblasts, osteocytes and odontoblasts with markedly elevated expression found in X-linked hypophosphatemic rickets (Hyp) osteoblasts and in oncogenic hypophosphatemic osteomalacia (OHO) tumors. Because these syndromes are associated with abnormalities in mineralization and renal phosphate excretion, we examined the effects of insect-expressed full-length human-MEPE (Hu-MEPE) on serum and urinary phosphate in vivo, 33 PO 4 uptake in renal proximal tubule cultures and mineralization of osteoblast cultures. Dose-dependent hypophosphatemia and hyperphosphaturia occurred in mice following intraperitoneal (IP) administration of Hu-MEPE (up to 400 μg kg -1 31 h -1 ), similar to mice given the phosphaturic hormone PTH (80 μg kg -1 31 h -1 ). Also the fractional excretion of phosphate (FEP) was stimulated by MEPE [65.0% (P < 0.001)] and PTH groups [53.3% (P < 0.001)] relative to the vehicle group [28.7% (SEM 3.97)]. In addition, Hu-MEPE significantly inhibited 33 PO 4 uptake in primary human proximal tubule renal cells (RPTEC) and a human renal cell line (Hu-CL8) in vitro (V max 53.4% inhibition; K m 27.4 ng/ ml, and V max 9.1% inhibition; K m 23.8 ng/ml, respectively). Moreover, Hu-MEPE dose dependently (50-800 ng/ml) inhibited BMP2-mediated mineralization of a murine osteoblast cell line (2T3) in vitro. Inhibition of mineralization was localized to a small (2 kDa) cathepsin B released carboxy-terminal MEPE peptide (protease-resistant) containing the acidic serineaspartate-rich motif (ASARM peptide). We conclude that MEPE promotes renal phosphate excretion and modulates mineralization.

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Section: Discussionmentioning

confidence: 99%

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Rowe

Kumagai²,

Gutiérrez³

et al. 2004

Bone

247

277

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“…FGFs 1-9 range in size from ϳ150 to 260 amino acid residues and have a conserved ϳ120-amino acid residue core with ϳ30 to 70% sequence identity (Ornitz and Itoh, 2001;Itoh and Ornitz, 2004). Based on their conserved amino acid sequences, Fgfs 10 -14 and 16 -23 were isolated by conducting a homology-based polymerase chain reaction or identified by homology-based searches in nucleotide sequence databases (Yamasaki et al, 1996;Smallwood et al, 1996;Miyake et al, 1998;Hoshikawa et al, 1998;Nishimura et al, 1999Nishimura et al, , 2000Ohmachi et al, 2000;Nakatake et al, 2001;Yamashita et al, 2000). In addition, Fgf15 was identified as a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx (McWhirter et al, 1997).…”

Section: Identification Of the Mouse Fgf Gene Familymentioning

confidence: 99%

Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

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356

313

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“…3,10,11 FGF23 was originally identified in the ventrolateral thalamic nucleus of the brain. 12 Although FGF23 mRNA is found in several tissues, this molecule is most abundantly expressed in bone, predominantly in osteocytes. [13][14][15][16][17][18] FGF23 essentially downregulates the serum levels of phosphate by inhibiting the absorption and reabsorption of phosphate from the gut and kidneys, respectively.…”

Section: Introductionmentioning

confidence: 99%

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

2014

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Fibroblast growth factor 23 (FGF23) and dentin matrix protein (DMP1) are hallmarks of osteocytes in bone. However, the mechanisms underlying the actions of DMP1 as a local factor regulating FGF23 and bone mineralization are not well understood. We first observed spatially distinct distributions of FGF23-and DMP1-positive osteocytic lacunae in rat femurs using immunohistochemistry. Three-dimensional immunofluorescence morphometry further demonstrated that the distribution and relative expression levels of these two proteins exhibited reciprocally reversed patterns especially in midshaft cortical bone. These in vivo findings suggest a direct role of DMP1 in FGF23 expression in osteocytes. We next observed that the inoculation of recombinant DMP1 in UMR-106 osteoblast/osteocyte-like cells and long-cultured MC3T3-E1 osteoblastic cells showed significant downregulation of FGF23 production. This effect was rescued by incubation with an focal adhesion kinase (FAK) inhibitor or MEK (mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)) inhibitor but not inhibitors of phosphoinositide 3-kinase or Rho kinase. Consistently, the levels of phosphorylated FAK, ERK and p38 were significantly elevated, indicating that exogenous DMP1 is capable of activating FAK-mediated MAPK signaling. These findings suggest that DMP1 is a local, direct and negative regulator of FGF23 production in osteocytes involved in the FAK-mediated MAPK pathway, proposing a relevant pathway that coordinates the extracellular environment of osteocytic lacunae and bone metabolism.

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Identification of a Novel Fibroblast Growth Factor, FGF-23, Preferentially Expressed in the Ventrolateral Thalamic Nucleus of the Brain

Cited by 505 publications

References 22 publications

MEPE has the properties of an osteoblastic phosphatonin and minhibin

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Functional evolutionary history of the mouse Fgf gene family

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

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