Differential Regulation of RGS-2 by Constant and Oscillating PTH Concentrations

PTH has diverse effects on bone metabolism: anabolic when given intermittently, catabolic when given continuously. The cellular mechanisms underlying the varying target cell response are not clear yet. PTH induces RGS-2, a member of the Regulator of G-protein Signaling protein family, via cAMP/PKA,...

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Bibliographic Details
Published in:Calcified tissue international 2009-04, Vol.84 (4), p.305-312
Main Authors: Hömme, M., Schaefer, F., Mehls, O., Schmitt, C. P.
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biomedical and Life Sciences
Bone and Bones - drug effects
Bone and Bones - metabolism
Bones
Cell Biology
Cell Line, Tumor
Cellular biology
Cyclic AMP-Dependent Protein Kinases - metabolism
Dose-Response Relationship, Drug
Dual Specificity Phosphatase 1 - metabolism
Dual Specificity Phosphatase 6 - metabolism
Endocrinology
Gene expression
Gene Expression Regulation
Hormones
Insulin-Like Growth Factor Binding Protein 5 - metabolism
Life Sciences
Matrix Metalloproteinase 13 - metabolism
Orthopedics
Osteoblasts - drug effects
Osteoblasts - metabolism
Parathyroid Hormone - pharmacology
Peptides
Rats
Receptor, Parathyroid Hormone, Type 1 - metabolism
RGS Proteins - metabolism
Signal transduction
Signal Transduction - drug effects
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Summary:PTH has diverse effects on bone metabolism: anabolic when given intermittently, catabolic when given continuously. The cellular mechanisms underlying the varying target cell response are not clear yet. PTH induces RGS-2, a member of the Regulator of G-protein Signaling protein family, via cAMP/PKA, and inactivates PKC-mediated signaling. To investigate intracellular signaling pathways with different PTH concentration-time patterns, we treated UMR 106-01 osteoblast-like cells in a perfusion system. PTH was administered intermittently (4 min/h, 10 −7  M) or continuously at an equivalent cumulative dose (6.6 × 10 −9  M). cAMP was measured using radioimmunoassay, mRNA levels using real-time rtPCR and ribonuclease protection assay, and protein levels using Western immunoblotting. A single PTH pulse transiently increased cAMP levels by 2000% ± 1200%. In contrast to continuous PTH exposure, cAMP induction remained unchanged with intermittent PTH, ruling out desensitization of the PTH receptor. In continuously perfused cells, RGS-2 abundance was three to five times higher than in cells intermittently exposed to PTH for up to 12 h. MKP-1 and -3 were significantly less induced with pulsatile PTH; exposure-mode-dependent differences in MMP-13 and IGFBP-5 were small. Pulsatile but not continuous PTH administration prevents PTHrP receptor desensitization and accumulation of RGS-2 in osteoblasts, which should preserve PKC-dependent signaling.
ISSN:0171-967X
1432-0827
DOI:10.1007/s00223-009-9222-1