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FGF23
in hypophosphatemic states
lessons learnt from a unique patient
Gabriele Haeusler, MDMedical University of Vienna
Austria
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Vasile-Joan B, born 1990
Healthy until age 13 years
Muscle weaknessBone painSeverely disabled at age 15 years
16 yrs
Laboratory findings:
Alkaline phosphatase 1652 U/L (<200)Serum phosphate 0,31-0,55 mmol/l (>0,9)Serum calcium 2,44 mmol/l (>2,25)PTH 39,8 pg/ml (15-60)25-OHVitD 67,8nmol/l (>50)1,25-OH2VitD 9pg/ml (>25)
Height 148 cm (<<3rd Pct)
Puberty: Tanner V
Photograph shown with permisiion of patient/family
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Rickets/ osteomalacia= Defect in mineralization
Mineralization: Deposition of hydroxyapatite Ca 10(Po4)6 OH 2
within collagen-I fibers
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serum phosphate
absorption
intestine
reabsorption
kidney
bone Intracellular space
FGF-23
PTH
Vit-D
MineralizationBone developmentSkeletal integrity
Component of DNA,RNA
Energy source (ATP)
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Farrow E & White KNat Rev Nephrol 6:207-217 (2010)
Jüppner-H et alJ Bone Miner Res 25: 2091—2097 (2010)
Bhattacharyya N et alTrends Endocrinol Metab 23: 610-618 (2012)
Sapir-Kohen & LivshitsIBMS BoneKEy 8: 286-300 (2011)
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Farrow, E. G. & White, K. E. (2010) Recent advances in renal phosphate handlingNat. Rev. Nephrol. doi:10.1038/nrneph.2010.17
Urakawa et al, Nature 2006Kurosi et al,J Biol Chem 2006
Weinman, J Biol Chem 2011Baum et al, Kidn Int 2005Shimada et al JBMR 2004 JCI 2004
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Figure 1 FGF23 regulatory systems in phosphate metabolism
Farrow, E. G. & White, K. E. (2010) Recent advances in renal phosphate handlingNat. Rev. Nephrol. doi:10.1038/nrneph.2010.17
Sapir-Kohen et al, IBMR BoneKEy 2011
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Bonewald& Wacker, Pediatr Nephrol 2013
FGF-23 production by osteocytes
Act as mechanosensors
Communicators
Orchestrators (bone remodelling)
Regulators of calcium and phosphate homeostasis
90-95% of all bone cells
FGF-23 not highly expressed in OCunder physiological conditions
But excessive expression in hypophosphatemic patients and CKD
Osteocytes
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Figure 1 FGF23 regulatory systems in phosphate metabolism
Farrow, E. G. & White, K. E. (2010) Recent advances in renal phosphate handlingNat. Rev. Nephrol. doi:10.1038/nrneph.2010.17
Sapir-Kohen et al, IBMR BoneKEy 2011
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Bhattacharyya N et al, Trends Endocrinology & Metabolism 2012
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Bhattacharyya N et al, Trends Endocrinology & Metabolism 2012
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Acquired forms
Tumor induced osteomalacia(TIO) > 300 cases
Tumor induced rickets<20 cases
Folpe 2004, Chong 2011
Recognition of a phosphaturic factor in 1959 by Prader et al
Shimada T et alCloning and characterization of FGF-23 as a causative factor of tumor-induced osteomalacia PNAS 98: 6500, 2001
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TIO- Diagnosis/ Detection
Histopathological entity (Folpe et al, 2004)
PMTMCT phosphaturic mesenchymal tumor mixed connective tissue variant
Variety of bone sites, size <1-14 cm
Detection rate about 50% ( MRI)
High resolution techniques (HR-MRI)
Somatostatin receptor imaging (Scintigraphy 111 In-octreotide)
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68-Gallium DOTATOC PET
HE, 1:25 mixed connective tissue type
JCEM 95; 4511-4517 (2010)
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Komaba, H. & Fukagawa, M. Nat Rev Nephrol (2012)
Serum FGF23
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0200400600800
10001200140016001800
18.12
.7.
3.11
.3.13
.315
.317
.3.19
.3. 2.4.
23.4.
16.7.
0,00,20,40,60,81,01,21,41,61,82,0
aPh U/L
phosphate mmol/l
0100200300400500600700800900
18.12
.7.
3.11
.3.13
.315
.317
.3.19
.3. 2.4.
23.4.
16.7.
050100150200250300350400450
FGF intact
FGF C-term
0
0,5
1
1,5
2
18.12
.7.
3.11
.3.13
.315
.317
.3.19
.3. 2.4.
23.4.
16.7.
00,511,522,53
S-Phosphate mmol/l
S-Calcium mmol/l
surgery
Immunohistochemistry FGF23
HE, 1:25 mixed connective tissue type
Oral Calcium 1-2g/d
JCEM 95; 4511-4517 (2010)
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Photograph shown with permisiion of patient/family
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JCEM 95; 4511-4517 (2010)
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Piglets 4-6 weeks
Manual extraction total growth plates
Collagenase digestion
Density gradient centrifugation
Monolayer culture 3D culture
Whole explant culture
Laser microdisection
Histo/cDNA Database
The porcine model for growth plate research
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Immunehistochemistry FGF23Pig, 4 weeks
Phalanx
10x 25x
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Raimann et al, Conn Tiss 2012
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Summary
FGF-23 is a central regulator of phosphate metabolismFGF-23 is involved in hypophosphatemic rickets, both hereditary and acquired
FGF-23 is the factor responsible for renal phosphate wasting in patients with TIO
The source of FGF-23 is bone, where FGF-23 is produced by bone cells underphysiological, and much more abundand, in pathological states
In TIO, therapy consists of surgical removal of the tumor, which, if complete, results in healing and complete recovery
In hereditary forms of hypophosphatemic rickets, therapy consists oforal phosphate and 1-25 OHD until new therapeutic agends are available
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Thank you for your attention