Expression and modulation of the parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acid in skin fibroblasts from patients with type Ib pseudohypoparathyroidism.
To explore the possibility that defects in the regulation of expression of the messenger ribonucleic acid (mRNA) coding for the PTH receptor could be involved in pseudohypoparathyroidism type Ib (PHP-Ib), PTH-induced cAMP production and PTH/PTH-related peptide (PTH-rp) receptor mRNA expression, measured using a ribonuclease protection assay, were compared in untreated and dexamethasone (dexa)-pretreated (5 x 10(-7) mol/L; 7 days) cultured skin fibroblasts from controls (n = 4) and patients with PHP-Ib (n = 6). In control fibroblasts, stimulation of cAMP production by PTH and expression of PTH/PTH-rp receptor mRNA were easily detectable and were not significantly affected by dexa pretreatment. In fibroblasts from three PHP-Ib patients demonstrating reduced PTH-induced cAMP production that was reversed by dexa, the level of basal PTH/PTH-rp receptor mRNA was also reduced, but increased to levels similar to those in control cells after dexa pretreatment. In fibroblasts from a patient with resistance to PTH not reversed by dexa, PTH/PTH-rp receptor mRNA expression was also significantly lower than that in control cells (18 +/- 13%; P < 0.001) and remained only 30 +/- 15% of that observed in control cells after dexa pretreatment (P < 0.001). In fibroblasts from two PHP-Ib patients expressing normal cAMP responsiveness to PTH before and after dexa treatment, the level of PTH/PTH-rp receptor mRNA was not different from that in control cells before or after dexa treatment. Thus, in all conditions where PTH-induced cAMP production by PHP-Ib fibroblasts was reduced, the abnormality could be explained by the reduced level of PTH/PTH-rp receptor mRNA in these cells. These results suggest that defects in the regulation of expression of the PTH/PTH-rp receptor mRNA, not structural defects in the receptor itself, explain the PTH resistance in PHP-Ib in the patients evaluated, but several different defects must exist.
Suarez
F
F
CNRS URA583, Hôpital Necker Enfants Malades, Faculté de Médecine, Paris, France.
Lebrun
J J
JJ
Lecossier
D
D
Escoubet
B
B
Coureau
C
C
Silve
C
C
D000591:Amino Acid Isomerases / Q000235:genetics; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase; D011547:Pseudohypoparathyroidism / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis*; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000235:genetics*
D002352:Carrier Proteins; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D003907:Dexamethasone; D000242:Cyclic AMP; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase