EXPRESSION AND MODULATION OF THE PARATHYROID-HORMONE (PTH) PTH-RELATED PEPTIDE RECEPTOR MESSENGER-RIBONUCLEIC-ACID IN SKIN FIBROBLASTS FROMPATIENTS WITH TYPE IB PSEUDOHYPOPARATHYROIDISM/

To explore the possibility that defects in the regulation of expressio n of the messenger ribonucleic acid (mRNA) coding for the PTH receptor could be involved in pseudohypoparathyroidism type Ib (PHP-Ib), PTH-i nduced cAMP production and PTH/PTH-related peptide (PTH-rp) receptor m RNA expression, measured using a ribonuclease protection assay, were c ompared in untreated and dexamethasone (dexa)-pretreated (5 x 10(-7) m ol/L; 7 days) cultured skin fibroblasts from controls (n = 4) and pati ents with PHP-Ib (n = 6). In control fibroblasts, stimulation of cAMP production by PTH and expression of PTH/PTH-rp receptor mRNA were easi ly 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 sim ilar to those in control cells after dexa pretreatment. In fibroblasts from a patient with resistance to PTH not reversed by dexa, PTH/PTH-r p receptor mRNA expression was also significantly lower than that in c ontrol cells (18 +/- 13%; P < 0.001) and remained only 30 +/- 15% of t hat observed in control cells after dexa pretreatment (P < 0.001). In fibroblasts from two PHP-Ib, patients expressing normal cAMP responsiv eness 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 a fter dexa treatment. Thus, in all conditions where PTH-induced cAMP pr oduction by PHP-Ib fibroblasts was reduced, the abnormality could be e xplained by the reduced level of PTH/PTH-rp receptor mRNA in these cel ls. These results suggest that defects in the regulation of expression of the PTH/PTH-rp receptor mRNA, not structural defects in the recept or itself, explain the PTH resistance in PHP-Ib, in the patients evalu ated, but several different defects must exist.