Vitamin D and dexamethasone inversely regulate parathyroid hormone-induced regulator of G protein signaling-2 expression in osteoblast-like cells.
The PTH/PTHrP receptor stimulates both adenylate cyclase- and phospholipase C-dependent signaling pathways via different G proteins. The biological actions of PTH on bone are modified by steroid hormones. PTH induces expression of regulator of G protein signaling (RGS)-2, a putative preferential inhibitor of G(q)-mediated phospholipase C activation. We investigated whether steroid hormones interfere with PTH signaling by modulating PTH-induced RGS-2 expression in osteoblast-like UMR 106-01 cells. PTH (1-34) rapidly and transiently induced expression of RGS-2 mRNA and protein via the cAMP/protein kinase A pathway within 30 min, with maximal protein abundance after 2 h. PTH-induced RGS-2 preferentially bound to Galpha(q), compared with Galpha(s) protein. 1,25-(OH)(2)D(3) pretreatment enhanced PTH-induced RGS-2 mRNA and protein accumulation, whereas dexamethasone preincubation had an attenuating effect. These effects were due to modulation of the RGS-2 gene transcription rate, which increased by 35% with 1,25-(OH)(2)D(3) and decreased by 63% with dexamethasone pretreatment. RGS-2 mRNA half-life was not affected by either steroid. The transcriptional effects of dexamethasone and 1,25-(OH)(2)D(3) were independent of PTH/PTHrP receptor activation and were not explained by effects on cAMP accumulation, cAMP response element-binding protein expression or phosphorylation, or the abundance of the osteoblast-specific transcription factor core-binding factor alpha (CBFa1/Runx2), a known activator of RGS-2 expression. In conclusion, glucocorticoids and 1,25-(OH)(2)D(3) inversely modulate PTH-induced RGS-2 gene transcription. Regulation of RGS-2 may constitute a novel mechanism by which steroids modulate signaling via the PTH/PTHrP receptor and other G protein-coupled receptors in bone.
Hömme
M
M
Division of Pediatric Nephrology, Heidelberg University Children's Hospital, 69120 Heidelberg, Germany.
Schmitt
C P
CP
Himmele
R
R
Hoffmann
G F
GF
Mehls
O
O
Schaefer
F
F
D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D050659:Core Binding Factor Alpha 1 Subunit; D050660:Core Binding Factors; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D012516:Osteosarcoma; D010281:Parathyroid Hormone / Q000494:pharmacology; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002120:Calcium Channel Agonists; D050659:Core Binding Factor Alpha 1 Subunit; D050660:Core Binding Factors; D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D020710:RGS Proteins; D012333:RNA, Messenger; C105345:Rgs2 protein, mouse; D014157:Transcription Factors; D005576:Colforsin; D003907:Dexamethasone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D002117:Calcitriol