Early lethality in Hyp mice with targeted deletion of Pth gene.
Although increased circulating levels of PTH with mild hypocalcemia has been reported in Hyp mice, hyperparathyroidism in X-linked hypophosphatemic rickets is postulated to arise from the standard use of phosphate salts, which induce chronic stimulation of PTH secretion. In this study, we sought to examine the role of PTH in the metabolic derangements associated with Hyp by generating hemizygous hypophosphatemic (Hyp/Y) mice homozygous for the Pth-null allele (Pth(-/-);Hyp/Y). Early postnatal lethality was observed in the Pth(-/-);Hyp/Y mice. Within the first 6 h, postpartum serum phosphorus increased to levels comparable to those in the Pth(-/-) mice, whereas in Hyp mice, it decreased during the first 48 h after birth. Serum calcium concentration started low after birth and remained reduced in both Pth(-/-);Hyp/Y and Pth(-/-) mice although more profoundly so in the former group, whereas in Hyp/Y mice, the levels were initially lower than but reached wild-type levels by 24 h. Circulating PTH levels in Hyp/Y mice were higher than wild-type levels throughout the first 48 h after birth and continued to be so well into adulthood. Twice-daily administration of PTH 1-34 to Pth(-/-);Hyp/Y newborn mice increased serum calcium levels and prevented their early demise. The findings here indicate that the cause of death in the Pth(-/-);Hyp/Y mice is severe hypocalcemia. A potential role for fibroblast growth factor 23 in promoting secondary hyperparathyroidism by suppressing renal 25-hydroxyvitamin D(3)-1alpha-hydroxylase (Cyp27b1) activity while increasing that of renal 25-hydroxyvitamin D(3) 24-hydroxylase (Cyp24) is proposed. Hyperparathyroidism, therefore, is an integral component in the pathophysiology of Hyp, and likely X-linked hypophosphatemic rickets and serves to prevent severe hypocalcemia in mice and perhaps in patients afflicted with the disorder.
Bai
Xiuying
X
Division of Endocrinology, Department of Medicine and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte Ste. Catherine Road, Montréal, Québec, Canada.
Miao
Dengshun
D
Goltzman
David
D
Karaplis
Andrew C
AC
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D017353:Gene Deletion; D006996:Hypocalcemia / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D007015:Hypophosphatemia, Familial / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000235:genetics* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000627:therapeutic use; D010641:Phenotype; D016879:Salvage Therapy; D012720:Severity of Illness Index; D012737:Sex Factors
D010281:Parathyroid Hormone; D010446:Peptide Fragments