title: Expression and modulation of the parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acid in skin fibroblasts from patients with type Ib pseudohypoparathyroidism.
abstract: 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.
authors.affiliation: CNRS URA583, Hôpital Necker Enfants Malades, Faculté de Médecine, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Suarez
authors.forename: J J
authors.initials: JJ
authors.lastname: Lebrun
authors.forename: D
authors.initials: D
authors.lastname: Lecossier
authors.forename: B
authors.initials: B
authors.lastname: Escoubet
authors.forename: C
authors.initials: C
authors.lastname: Coureau
authors.forename: C
authors.initials: C
authors.lastname: Silve
mesh_terms: 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*
chemical_list: 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