Human PTH gene regulation in vivo using transgenic mice.
To study the regulation of the human PTH (hPTH) gene in vivo, we generated transgenic mice with the hPTH gene expressed in the mouse parathyroid using a bacterial artificial chromosome (BAC) containing the hPTH gene within its 144-kb chromosomal region. The BAC construct maintains the native hPTH gene surrounding sequences and isolates it from positional effects. The transgenic mice had normal levels of serum mouse PTH (mPTH) in addition to both intact and bioactive hPTH. Despite the presence of both mPTH and hPTH, serum calcium and 1,25(OH)(2) vitamin D levels were normal. The lack of response to hPTH may be due to tachyphylaxis of the mPTH receptor (PTH1R) and/or impaired recognition of the mPTH1R. In contrast, the regulation of hPTH levels in the mouse was intact. A calcium-depleted diet increased serum mPTH and both intact and bioactive hPTH. mPTH and hPTH mRNA levels were also markedly increased. The calcimimetic R-568 dramatically decreased mPTH and hPTH serum levels. Administered recombinant fibroblast growth factor (FGF)23 decreased hPTH. Therefore, the regulation of hPTH gene expression and serum hPTH levels is intact in the transgenic mice, indicating preservation of the signal transduction of the parathyroid calcium receptor and the Klotho-FGF receptor between mouse and man.
Lavi-Moshayoff
Vardit
V
Nephrology Services, Hadassah Hebrew University Medical Center, P. O. Box 12000, Jerusalem, Israel 91120.
Silver
Justin
J
Naveh-Many
Tally
T
D000367:Age Factors; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000819:agonists / Q000097:blood; D022202:Chromosomes, Artificial, Bacterial; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D008822:Mice, Transgenic; D010281:Parathyroid Hormone / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010627:Phenethylamines; D011437:Propylamines; D012333:RNA, Messenger / Q000097:blood; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013618:Tachyphylaxis
D000814:Aniline Compounds; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D044169:Receptors, Calcium-Sensing; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol; D002118:Calcium