Phex cDNA cloning from rat bone and studies on phex mRNA expression: tissue-specificity, age-dependency, and regulation by insulin-like growth factor (IGF) I in vivo.
Phosphate regulating gene with homology to endopeptidases on the X chromosome (Phex) inactivating mutations cause X-linked hypophosphatemia (XLH). The disorder is characterized by decreased renal phosphate (Pi) reabsorption in both humans and mice, in the latter shown to be due to a reduction in mRNA and protein of type II sodium-dependent phosphate cotransporter (NadPi-II). To gain insight into the physiological role of Phex, we cloned the rat cDNA and examined tissue-specific and age-dependent mRNA expression. The rat full-length cDNA (2247 nucleotides) shares 96 and 90% identity with the mouse and human cDNA, respectively. We found 6.6 kb Phex transcripts in calvarial bone and lungs, and a weaker signal in liver of newborn rats. In adult animals, Phex mRNA signals were weaker in bone and lungs and absent in liver. Phex mRNA expression in bones and NadPi-I and -II cotransporter mRNA expression in kidney were also determined in hypophysectomized rats. These rats, which lack GH and IGF I, stop growing and exhibit decreased serum Pi levels. Treatment during 6 days with IGF I stimulated growth and increased serum Pi. Phex and NadPi-II cotransporter mRNA levels were higher in IGF I than in vehicle-treated animals, while mRNA expression of NadPi-I, 1alpha-hydroxylase and 24-hydroxylase and serum levels of calcitriol remained unaffected. Age-dependency of Phex expression suggests a role for Phex in Pi retention during growth. Moreover, our findings indicate that an increase in Phex expression in bones under the influence of IGF I may contribute to increased serum Pi by enhancing renal phosphate reabsorption. Because IGF I treatment increased NadPi-II mRNA expression and serum Pi, IGF I appears to act at least partially at pretranslational levels to increase NadPi-II mediated renal Pi retention in growing rats.
Zoidis
E
E
Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital, CH-8091, Zürich, Switzerland. ndozoe@usz.unizh.ch
Zapf
J
J
Schmid
C
C
D000375:Aging / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001835:Body Weight; D001842:Bone and Bones / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D019382:Human Growth Hormone / Q000494:pharmacology; D007015:Hypophosphatemia, Familial / Q000235:genetics; D007016:Hypophysectomy; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D008969:Molecular Sequence Data; D009928:Organ Specificity; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010710:Phosphates / Q000097:blood; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters
D002352:Carrier Proteins; D018076:DNA, Complementary; D010710:Phosphates; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; C506232:Phex protein, mouse; C506229:Phex protein, rat