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

Robert F. Spurney, Patrick J. Flannery, Sanford C. Garner, Krairerk Athirakul, Shiguang Liu, Farshid Guilak, Leigh Quarles

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1361-1371
Number of pages11
JournalJournal of Clinical Investigation
Volume109
Issue number10
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

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G-Protein-Coupled Receptor Kinases
Anabolic Agents
Osteoblasts
Phosphotransferases
G-Protein-Coupled Receptors
Transgenic Mice
Bone Remodeling
Phosphorylation
Parathyroid Hormone Receptor Type 1
Osteocalcin
Osteoclasts
Parathyroid Hormone
Transgenes
Osteogenesis
Skull
Bone Density
Cell Culture Techniques
Ligands
Bone and Bones
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Spurney, R. F., Flannery, P. J., Garner, S. C., Athirakul, K., Liu, S., Guilak, F., & Quarles, L. (2002). Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts. Journal of Clinical Investigation, 109(10), 1361-1371. https://doi.org/10.1172/JCI0214663

Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts. / Spurney, Robert F.; Flannery, Patrick J.; Garner, Sanford C.; Athirakul, Krairerk; Liu, Shiguang; Guilak, Farshid; Quarles, Leigh.

In: Journal of Clinical Investigation, Vol. 109, No. 10, 01.01.2002, p. 1361-1371.

Research output: Contribution to journalArticle

Spurney, RF, Flannery, PJ, Garner, SC, Athirakul, K, Liu, S, Guilak, F & Quarles, L 2002, 'Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts', Journal of Clinical Investigation, vol. 109, no. 10, pp. 1361-1371. https://doi.org/10.1172/JCI0214663
Spurney RF, Flannery PJ, Garner SC, Athirakul K, Liu S, Guilak F et al. Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts. Journal of Clinical Investigation. 2002 Jan 1;109(10):1361-1371. https://doi.org/10.1172/JCI0214663
Spurney, Robert F. ; Flannery, Patrick J. ; Garner, Sanford C. ; Athirakul, Krairerk ; Liu, Shiguang ; Guilak, Farshid ; Quarles, Leigh. / Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts. In: Journal of Clinical Investigation. 2002 ; Vol. 109, No. 10. pp. 1361-1371.
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