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Unmasking the osteoinductive effects of a G-protein-coupled receptor (GPCR) kinase (GRK) inhibitor by treatment with PTH(1-34).

Publication ,  Journal Article
Wang, L; Quarles, LD; Spurney, RF
Published in: J Bone Miner Res
October 2004

UNLABELLED: The effects of GPCR systems in bone are regulated by a family of enzymes termed GRKs. We found that (1) GRK inhibition in osteoblasts has age-dependent effects on bone mass, and (2) the anabolic actions of GRK inhibition are revealed by treatment with PTH(1-34). INTRODUCTION: The effects of G-protein-coupled receptor (GPCR) systems in bone are modulated by a family of enzymes termed GPCR kinases (GRKs). These enzymes directly phosphorylate GPCR substrate and desensitize receptor signaling. We previously found that expression of a GRK inhibitor in osteoblasts using transgenic (TG) technologies enhanced bone remodeling, and in turn, increased BMD in 6-week-old TG mice compared with non-TG littermate controls, presumably because of enhanced GPCR function. The aim of this study was to determine the age-dependent effects of the transgene. MATERIALS AND METHODS: BMD was monitored in TG mice and in controls at 6-week, 3-month, and 6-month time-points. To determine if the transgene enhanced responsiveness of bone to parathyroid hormone (PTH), we measured cyclic adenosine monophosphate (cAMP) generation by mouse calvaria ex vivo as well as the effects of treatment with PTH(1-34) on BMD, bone histomorphometry, and expression of the PTH-responsive gene RANKL in both TG mice and non-TG controls. RESULTS: Consistent with our previous findings, we found that BMD was increased in TG mice compared with controls at 6 weeks of age. The increase in BMD was most prominent in trabecular-rich lumbar spine and was not observed in cortical bone of the femoral shaft. In contrast to younger animals, however, BMD in older TG mice was not statistically different compared with non-TG mice at 3 months of age and was similar to non-TG animals at 6 months of age. The GRK inhibitor seemed to promote GPCR activation in older mice, however, because (1) PTH-induced cAMP generation by mouse calvaria ex vivo was enhanced in TG mice compared with controls, (2) GRK inhibition increased responsiveness of lumbar spine to the osteoinductive actions of PTH(1-34), and (3) the enhanced anabolic effect of PTH(1-34) was associated with increased expression of the PTH-responsive gene RANKL in calvaria of the TG animals. Bone histomorphometry confirmed that PTH(1-34) increased trabecular bone volume in TG mice and found that this increase in bone mass was caused by enhanced bone formation, predominantly as a result of an increase in the mineral apposition rate (MAR). CONCLUSIONS: These data suggest that the anabolic effects of GRK inhibition are age dependent. The osteoinductive actions of the GRK inhibitor are, however, unmasked by treatment with PTH(1-34).

Duke Scholars

Published In

J Bone Miner Res

DOI

ISSN

0884-0431

Publication Date

October 2004

Volume

19

Issue

10

Start / End Page

1661 / 1670

Location

England

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Receptors, Tumor Necrosis Factor
  • Receptors, Parathyroid Hormone
  • Receptors, Cytoplasmic and Nuclear
  • Receptor Activator of Nuclear Factor-kappa B
  • RNA, Messenger
  • RANK Ligand
  • Peptide Fragments
  • Parathyroid Hormone
  • Osteoprotegerin
 

Citation

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Wang, L., Quarles, L. D., & Spurney, R. F. (2004). Unmasking the osteoinductive effects of a G-protein-coupled receptor (GPCR) kinase (GRK) inhibitor by treatment with PTH(1-34). J Bone Miner Res, 19(10), 1661–1670. https://doi.org/10.1359/JBMR.040708
Wang, Liming, L Darryl Quarles, and Robert F. Spurney. “Unmasking the osteoinductive effects of a G-protein-coupled receptor (GPCR) kinase (GRK) inhibitor by treatment with PTH(1-34).J Bone Miner Res 19, no. 10 (October 2004): 1661–70. https://doi.org/10.1359/JBMR.040708.
Wang, Liming, et al. “Unmasking the osteoinductive effects of a G-protein-coupled receptor (GPCR) kinase (GRK) inhibitor by treatment with PTH(1-34).J Bone Miner Res, vol. 19, no. 10, Oct. 2004, pp. 1661–70. Pubmed, doi:10.1359/JBMR.040708.
Journal cover image

Published In

J Bone Miner Res

DOI

ISSN

0884-0431

Publication Date

October 2004

Volume

19

Issue

10

Start / End Page

1661 / 1670

Location

England

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Receptors, Tumor Necrosis Factor
  • Receptors, Parathyroid Hormone
  • Receptors, Cytoplasmic and Nuclear
  • Receptor Activator of Nuclear Factor-kappa B
  • RNA, Messenger
  • RANK Ligand
  • Peptide Fragments
  • Parathyroid Hormone
  • Osteoprotegerin