Targeted overexpression of G protein-coupled receptor kinase-2 in osteoblasts promotes bone loss

Liming Wang, Shiguang Liu, Leigh Quarles, Robert F. Spurney

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

To investigate the role of G protein-coupled receptor kinases (GRKs) in regulating bone formation in vivo, we overexpressed the potent G protein-coupled receptor (GPCR) regulator GRK2 in osteoblasts, using the osteocalcin gene-2 promoter to target expression to osteoblastic cells. Using the parathyroid hormone (PTH) receptor as a model system, we found that overexpression of GRK2 in osteoblasts attenuated PTH-induced cAMP generation by mouse calvaria ex vivo. This decrease in GPCR responsiveness was associated with a reduction in bone mineral density (BMD) in transgenic (TG) mice compared with non-TG littermate controls. The decrease in BMD was most prominent in trabecular-rich lumbar spine and was not observed in cortical bone of the femoral shaft. Quantitative computed tomography indicated that the loss of trabecular bone was due to a decrease in trabecular thickness, with little change in trabecular number. Histomorphometric analyses confirmed the decrease in trabecular bone volume and demonstrated reduced bone remodeling, as evidenced by a decrease in osteoblast numbers and osteoblast-mediated bone formation. Osteoclastic activity also appeared to be reduced because urinary excretion of the osteoclastic activity marker deoxypyridinoline was decreased in TG mice compared with control animals. Consistent with reduced coupling of osteoblast-mediated bone formation to osteoclastic bone resorption, mRNA levels of both osteoprotegrin and receptor activator of NF-κB ligand were altered in calvaria of TG mice in a pattern that would promote a low rate of bone remodeling. Taken together, these data suggest that enhancing GRK2 activity and consequently reducing GPCR activity in osteoblasts produces a low bone-turnover state that reduces bone mass.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume288
Issue number4 51-4
DOIs
StatePublished - Apr 1 2005
Externally publishedYes

Fingerprint

G-Protein-Coupled Receptor Kinase 2
Osteoblasts
Bone and Bones
Bone Remodeling
G-Protein-Coupled Receptors
Osteogenesis
Transgenic Mice
Skull
Bone Density
G-Protein-Coupled Receptor Kinases
Parathyroid Hormone Receptor Type 1
Osteocalcin
Bone Resorption
Thigh
Parathyroid Hormone
Spine
Tomography
Ligands
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Targeted overexpression of G protein-coupled receptor kinase-2 in osteoblasts promotes bone loss. / Wang, Liming; Liu, Shiguang; Quarles, Leigh; Spurney, Robert F.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 288, No. 4 51-4, 01.04.2005.

Research output: Contribution to journalArticle

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