IGF-I and GH stimulate Phex mRNA expression in lungs and bones and 1,25-dihydroxyvitamin D(3) production in hypophysectomized rats.
OBJECTIVE
X-linked hypophosphatemia, a renal phosphate (Pi)-wasting disorder with defective bone mineralization, is caused by mutations in the PHEX gene (a Pi-regulating gene with homology to endopeptidases on the X chromosome). We wondered whether changes in Phex and neprilysin (NEP) (another member of the family of zinc endopeptidases) mRNA expression could be observed in relation to vitamin D and Pi metabolism during GH- and IGF-I-stimulated growth of hypophysectomized rats.


METHODS
Animals were infused s.c. for 2 days with vehicle, 200 mU (67 microg) GH or 300 microg IGF-I/rat per 24 h. We determined serum osteocalcin and osteocalcin mRNA in bone, Phex mRNA in bone and lungs, serum 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) and serum Pi levels, and renal expression of 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase), of 25-hydroxyvitamin D(3)-24-hydroxylase (24-hydroxylase) and of the Na-dependent Pi-cotransporter type I and II (Na(d)Pi-I and -II).


RESULTS
As compared with vehicle-treated controls, body weight and tibial epiphyseal width significantly increased in GH- and IGF-I-treated animals. Serum osteocalcin and osteocalcin mRNA levels in bone, Phex mRNA in bone and lungs, serum 1,25-(OH)(2)D(3) and renal 1alpha-hydroxylase mRNA rose concomitantly, whereas expression of NEP in lungs was barely affected and renal 24-hydroxylase mRNA decreased. Na(d)Pi-I and -II gene expression in the kidney and serum Pi levels remained unchanged.


CONCLUSIONS
Our findings suggest a coordinate regulation of Phex mRNA expression in lungs and bone and vitamin D metabolism during GH- and IGF-I-stimulated growth.
Zoidis
Evangelos
E
Division of Endocrinology and Diabetes, Department of Internal Medicine, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. ndozoe@usz.unizh.ch
Gosteli-Peter
Martina
M
Ghirlanda-Keller
Claudia
C
Meinel
Lorenz
L
Zapf
Jürgen
J
Schmid
Christoph
C
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D001846:Bone Development / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002117:Calcitriol / Q000096:biosynthesis*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D013006:Growth Hormone / Q000494:pharmacology*; D007016:Hypophysectomy; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010710:Phosphates / Q000378:metabolism*; D014176:Protein Biosynthesis; D011506:Proteins; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018076:DNA, Complementary; D010710:Phosphates; D011506:Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506229:Phex protein, rat; D002117:Calcitriol