Dexamethasone increases preproparathyroid hormone messenger RNA in human hyperplastic parathyroid cells in vitro.
To determine if parathyroid hormone release in man is directly stimulated by glucocorticoids, dispersed human parathyroid cells from hyperplastic glands obtained from eight renal transplant recipients were studied in vitro. Dexamethasone (10(-11) to 10(-6) mol l-1) increased PTH release in a time- and dose-dependent manner. A plateau was reached at 10(-8) mol l-1 (1015 +/- 149 vs. 230 +/- 27 pg 10(-4) cells for control value, after 24 h incubation; P less than 0.0001). An interaction with a glucocorticoid receptor was suggested since 10(-6) mol l-1 RU 486 blunted the dexamethasone-induced PTH release. By Northern blot analysis, dexamethasone was found to increase the amount of preproPTH mRNA in these cells. The effect of dexamethasone was probably at the gene level since (1) 1,25 dihydroxy vitamin D3 inhibited both iPTH and preproPTH mRNA increases induced by dexamethasone and (2) alpha-amanitin (1,25 micrograms ml-1) also completely suppressed the dexamethasone-induced PTH release. Thus, for the first time, we demonstrate that dexamethasone induces an increase of PTH synthesis, probably by increasing PTH gene transcription. This effect may play an important pathogenic role in persisting hyperparathyroidism and steroid-induced bone complications in renal transplant recipients.
Peraldi
M N
MN
Unité INSERM U64, Hôpital Tenon, Paris, France.
Rondeau
E
E
Jousset
V
V
el M'Selmi
A
A
Lacave
R
R
Delarue
F
F
Garel
J M
JM
Sraer
J D
JD
D000546:Amanitins / Q000494:pharmacology; D001667:Binding, Competitive; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D066298:In Vitro Techniques; D015735:Mifepristone / Q000494:pharmacology; D010280:Parathyroid Glands / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000235:genetics* / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology; D013997:Time Factors
D000546:Amanitins; D010281:Parathyroid Hormone; D011498:Protein Precursors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; C019056:preproparathormone; D003907:Dexamethasone