RGD Reference Report - Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts. - Rat Genome Database

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Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts.

Authors: Spurney, RF  Flannery, PJ  Garner, SC  Athirakul, K  Liu, S  Guilak, F  Quarles, LD 
Citation: Spurney RF, etal., J Clin Invest 2002 May;109(10):1361-71.
RGD ID: 625698
Pubmed: PMID:12021252   (View Abstract at PubMed)
PMCID: PMC150976   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI14663   (Journal Full-text)

G protein-coupled receptors (GPCRs) play a key role in regulating bone remodeling. Whether GPCRs exert anabolic or catabolic osseous effects may be determined by the rate of receptor desensitization in osteoblasts. Receptor desensitization is largely mediated by direct phosphorylation of GPCR proteins by a family of enzymes termed GPCR kinases (GRKs). We have selectively manipulated GRK activity in osteoblasts in vitro and in vivo by overexpressing a GRK inhibitor. We found that expression of a GRK inhibitor enhanced parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor-stimulated cAMP generation and inhibited agonist-induced phosphorylation of this receptor in cell culture systems, consistent with attenuation of receptor desensitization. To determine the effect of GRK inhibition on bone formation in vivo, we targeted the expression of a GRK inhibitor to mature osteoblasts using the mouse osteocalcin gene 2 (OG2) promoter. Transgenic mice demonstrated enhanced bone remodeling as well as enhanced urinary excretion of the osteoclastic activity marker dexoypyridinoline. Both osteoprotegrin and OPG ligand mRNA levels were altered in calvaria of transgenic mice in a pattern that would promote osteoclast activation. The predominant effect of the transgene, however, was anabolic, as evidenced by an increase in bone density and trabecular bone volume in the transgenic mice compared with nontransgenic littermate controls.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
G protein-coupled receptor signaling pathway  IDA 625698 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Grk2  (G protein-coupled receptor kinase 2)

Objects referenced in this article
Gene Grk3 G protein-coupled receptor kinase 3 Rattus norvegicus

Additional Information