FGF23

in hypophosphatemic states

lessons learnt from a unique patient

Gabriele Haeusler, MDMedical University of Vienna

Austria

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

Rickets/ osteomalacia= Defect in mineralization

Mineralization: Deposition of hydroxyapatite Ca 10(Po4)6 OH 2

within collagen-I fibers

serum phosphate

absorption

intestine

reabsorption

kidney

bone Intracellular space

FGF-23

PTH

Vit-D

MineralizationBone developmentSkeletal integrity

Component of DNA,RNA

Energy source (ATP)

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)

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

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

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

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

Bhattacharyya N et al, Trends Endocrinology & Metabolism 2012

Bhattacharyya N et al, Trends Endocrinology & Metabolism 2012

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

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)

68-Gallium DOTATOC PET

HE, 1:25 mixed connective tissue type

JCEM 95; 4511-4517 (2010)

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

Serum FGF23

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)

Photograph shown with permisiion of patient/family

JCEM 95; 4511-4517 (2010)

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

Immunehistochemistry FGF23Pig, 4 weeks

Phalanx

10x 25x

Raimann et al, Conn Tiss 2012

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

Thank you for your attention