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Published on: June 9, 2023
Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts
Robert F Spurney1, Patrick J Flannery, Sanford C Garner
1Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Administration Medical Centers, North Carolina 27710, USA. spurn002@mc.duke.edu
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.
Insights
Inhibiting GPCR kinases (GRKs) in osteoblasts enhances bone formation by slowing receptor desensitization. This study shows GRK inhibition promotes anabolic bone effects, increasing bone density and volume.
Area of Science:
- Bone biology and endocrinology
- G protein-coupled receptor (GPCR) signaling
- Skeletal remodeling regulation
Background:
- G protein-coupled receptors (GPCRs) are crucial for bone remodeling.
- Receptor desensitization rate influences GPCRs' anabolic or catabolic effects on bone.
- GPCR kinases (GRKs) mediate receptor desensitization via phosphorylation.
Purpose of the Study:
- To investigate the role of GPCR kinase (GRK) activity in osteoblast function.
- To determine the impact of GRK inhibition on bone remodeling and formation.
- To explore the potential of modulating GRK activity for therapeutic bone anabolic effects.
Main Methods:
- Selective manipulation of GRK activity in osteoblasts using a GRK inhibitor.
- In vitro studies assessing cAMP generation and receptor phosphorylation.
- In vivo studies using transgenic mice expressing a GRK inhibitor under the osteocalcin gene 2 (OG2) promoter.
Main Results:
- GRK inhibition enhanced parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor-stimulated cAMP generation in vitro.
- Agonist-induced receptor phosphorylation was inhibited, indicating attenuated desensitization.
- Transgenic mice showed increased bone remodeling, elevated urinary deoxypyridinoline, and altered osteoprotegrin/OPG ligand mRNA levels.
- Predominant anabolic effect observed: increased bone density and trabecular bone volume in transgenic mice.
Conclusions:
- GPCR desensitization rate in osteoblasts is a critical determinant of bone remodeling.
- Inhibition of GRKs in osteoblasts attenuates receptor desensitization and promotes anabolic bone effects.
- Targeting GRK activity represents a potential strategy for enhancing bone formation and treating bone loss conditions.
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