1. Medical University of Vienna
FGF23
in hypophosphatemic states
lessons learnt from a unique patient
Gabriele Haeusler, MD
Medical University of Vienna
Austria

2. Healthy until age 13 years Muscle weakness Bone pain
Vasile-Joan B, born 1990
Healthy until age 13 years
Muscle weakness
Bone pain
Severely disabled at age 15 years
16 yrs
Laboratory findings:
Alkaline phosphatase 1652 U/L (<200)
Serum phosphate ,31-0,55 mmol/l (>0,9)
Serum calcium ,44 mmol/l (>2,25)
PTH ,8 pg/ml (15-60)
25-OHVitD ,8nmol/l (>50)
1,25-OH2VitD pg/ml (>25)
Photograph shown with permisiion of patient/family
Height 148 cm (<<3rd Pct)
Puberty: Tanner V

3. within collagen-I fibers
Rickets/ osteomalacia= Defect in mineralization
Mineralization: Deposition of hydroxyapatite Ca 10(Po4)6 OH 2
within collagen-I fibers

4. PTH FGF-23 Vit-D bone Intracellular space serum phosphate reabsorption
Mineralization
Bone development
Skeletal integrity
Component of DNA,RNA
Energy source (ATP)
intestine
kidney

5. Bhattacharyya N et al
Trends Endocrinol Metab 23: (2012)
Farrow E & White K
Nat Rev Nephrol 6: (2010)
Jüppner-H et al
J Bone Miner Res 25: 2091—2097 (2010)
Sapir-Kohen & Livshits
IBMS BoneKEy 8: (2011)

6. Nat. Rev. Nephrol. doi:10.1038/nrneph.2010.17
Urakawa et al, Nature 2006
Kurosi et al,J Biol Chem 2006
Weinman, J Biol Chem 2011
Baum et al, Kidn Int 2005
Shimada et al JBMR 2004
JCI 2004
Farrow, E. G. & White, K. E. (2010) Recent advances in renal phosphate handling
Nat. Rev. Nephrol. doi: /nrneph

7. Figure 1 FGF23 regulatory systems in phosphate metabolism
Farrow, E. G. & White, K. E. (2010) Recent advances in renal phosphate handling
Nat. Rev. Nephrol. doi: /nrneph
Sapir-Kohen et al, IBMR BoneKEy 2011

8. Osteocytes 90-95% of all bone cells Act as mechanosensors
Communicators
Orchestrators (bone remodelling)
Regulators of calcium and
phosphate homeostasis
FGF-23 not highly expressed in OC
under physiological conditions
But excessive expression in
hypophosphatemic patients and CKD
FGF-23 production by osteocytes
Bonewald& Wacker, Pediatr Nephrol 2013

9. Figure 1 FGF23 regulatory systems in phosphate metabolism
Farrow, E. G. & White, K. E. (2010) Recent advances in renal phosphate handling
Nat. Rev. Nephrol. doi: /nrneph
Sapir-Kohen et al, IBMR BoneKEy 2011

10. Bhattacharyya N et al, Trends Endocrinology & Metabolism 2012

11. Bhattacharyya N et al, Trends Endocrinology & Metabolism 2012

12. Acquired forms Shimada T et al
Recognition of a phosphaturic factor in 1959 by Prader et al
Shimada T et al
Cloning and characterization of FGF-23 as a causative factor of tumor-induced osteomalacia PNAS 98: 6500, 2001
Tumor induced rickets
<20 cases
Tumor induced osteomalacia
(TIO) > 300 cases
Folpe 2004, Chong 2011

13. 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)

14. 68-Gallium DOTATOC PET HE, 1:25 mixed connective tissue type
JCEM 95; (2010)

15. Komaba, H. & Fukagawa, M. Nat Rev Nephrol (2012)
Serum FGF23
Komaba, H. & Fukagawa, M. Nat Rev Nephrol (2012)

16. surgery
Immunohistochemistry FGF23
Oral Calcium 1-2g/d
HE, 1:25 mixed connective tissue type
JCEM 95; (2010)

17. Photograph shown with permisiion of patient/family

18. JCEM 95; (2010)

19. The porcine model for growth plate research
Piglets 4-6 weeks
Histo/cDNA Database
Manual extraction total growth plates
Whole explant culture
Collagenase digestion
Laser microdisection
Density gradient centrifugation
Monolayer culture
3D culture

20. Immunehistochemistry FGF23 Pig, 4 weeks
Phalanx
10x
25x

21. Raimann et al, Conn Tiss 2012

22. Summary FGF-23 is a central regulator of phosphate metabolism
FGF-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 under
physiological, 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 of
oral phosphate and 1-25 OHD until new therapeutic agends are available

23. Thank you for your attention