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sHPT: Bisheriges Konzept
Adapted from Quarles, JCI 2008
1,25(OH)2D3 – iPTH
PO4- und FGF23
Prie et al.
FGF 23 / Klotho
ASN 2009
60 Poster FGF23
35 Poster Klotho
Adapted from Quarles, JCI 2008
FGF23/ Klotho - Achse
Adapted from Quarles, JCI 2008
FGF23 - Fakten
Knochen ist HORMONELL aktiv !
Wirkung von FGF23:
• induziert Phosphaturie
• hemmt die renale 1,25D Produktion
Stimuli der FGF 23 Produktion:
• Vermehrte Phosphatzufuhr
• 1,25D
FGF 23 bei CKD
FGF23 - Phosphatbilanz
- ohne Vit. D
- Quartile aus 10.000 Pat.
- daraus ausgewählt:
n=200 Pat. starben in 1 Jahr
n=200 Kontrollen überlebten 1 Jahr
sHPT: Neues Konzept
Wetmore et al., Nature Clinical Practice Nephrology 01/2009
FGF23 - Nebenschilddrüse
Ben-Dov et al., JCI 2007Silver et al., Kidney int. 2009
sHPT: Neues Konzept
Prie et al.
overallPO4
- 3,7-4,5 mg/dl
HR=0,72
p=0,03
- Früher Beginn einer Phosphatbindertherapie
- Phosphatbinder n= 3555
- Kein Phosphatbinder n=5055
Ausblick ?
CKD 3 und 4
6 Wochen PO4--Binder-Titrationsphase
2 Wochen Auswaschphase
Ausblick ?
sHPT: Neues Konzept
Prie et al.
sHPT:
Nebenschilddrüse FGF23 resistent ?
sHPT:
Nebenschilddrüse FGF23 resistent ?
RBK- Forschungs-Projekt Gewebedatenbank Nebenschilddrüse:
Expressionsmuster zahlreicher neuerer Faktoren (FGF-R, Klotho,
Vit.D-R, Ca-S-R, PTH, 1-alpha-Hydroxylase, …)
und
Korrelationen
mit klinischen Parametern
Zusammenfassung
Prie et al.
ASN 2009 Abstract F-PO1871]: Looping the Bone-Parathyroid
Axis: PTH Increases FGF23 Expression
Vardit Lavi-Moshayoff, Gilad Wasserman, Tally Naveh-Many, Justin Silver Nephrology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Fibroblast growth factor 23 (FGF23) acts on the parathyroid to decrease PTH expression. We now report that PTH increases FGF23 expression. Adenine high Pi induced CKD rats at four days, had a marked increase in both serum PTH and FGF23 with no changes in serum calcium, Pi and 1,25(OH)2D (1,25D) suggesting a direct relationship between PTH and FGF23. Parathyroidectomy (PTX) corrected the high serum FGF23 levels. Remarkably, PTX completely prevented the rise in FGF23 in rats subsequently fed the adenine high Pi diet. Therefore, PTX both corrects and prevents the increased FGF23 of CKD. Minipump infusion of PTH increased serum FGF23, calvaria FGF23 mRNA and serum calcium levels in normal mice. To understand the mechanism of the direct effect of PTH on FGF23 we studied the expression of the upstream negative regulators of FGF23 in vivo and in vitro. CKD led to increased calvaria FGF23 mRNA levels and decreased Phex and DMP1 mRNA levels. In osteoblast-like UMR106 cells, PTH increased FGF23 mRNA levels and markedly decreased DMP1 (dentine matrix protein1), Phex(phosphate regulating hormone with homology to endopeptidase on the X chromosome) and MEPE (matrix extracellular phosphoglycoprotein) mRNA levels up to 48 h. DMP1 and MEPE increase Phex expression which leads to FGF23 protein degradation. The decrease in DMP1, MEPE and Phex by PTH would increase FGF23 protein levels. Our results show that in addition, PTH increases FGF23 gene expression. The effect of PTH on FGF23 mRNA may be either direct or mediated by Phex, DMP1 and/or MEPE. Therefore, PTH increases FGF23 expression in vivo and in vitro which together with the effect of FGF23 to decrease PTH completes a novel bone-parathyroid endocrine loop.
Zusammenfassung
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Prie et al.
