Conditional expression of a Gi-coupled receptor in osteoblasts results in trabecular osteopenia

Peng, J., Bencsik, M., Louie, A., Lu, W., Millard, S., Nguyen, P., Burghardt, A., Majumdar, S., Wronski, T. J., Halloran, B., Conklin, B. R. and Nissenson, R. A. (2008) Conditional expression of a Gi-coupled receptor in osteoblasts results in trabecular osteopenia. Endocrinology, 149 3: 1329-1337. doi:10.1210/en.2007-0235

Author Peng, J.
Bencsik, M.
Louie, A.
Lu, W.
Millard, S.
Nguyen, P.
Burghardt, A.
Majumdar, S.
Wronski, T. J.
Halloran, B.
Conklin, B. R.
Nissenson, R. A.
Title Conditional expression of a Gi-coupled receptor in osteoblasts results in trabecular osteopenia
Journal name Endocrinology   Check publisher's open access policy
ISSN 0013-7227
Publication date 2008-03
Sub-type Article (original research)
DOI 10.1210/en.2007-0235
Volume 149
Issue 3
Start page 1329
End page 1337
Total pages 9
Place of publication Chevy Chase, MD, United States
Publisher The Endocrine Society
Language eng
Formatted abstract
G protein-coupled receptors (GPCRs) coupled to activation of Gs, such as the PTH1 receptor (PTH1R), have long been known to regulate skeletal function and homeostasis. However, the role of GPCRs coupled to other G proteins such as Gi is not well established. We used the tet-off system to regulate the expression of an activated Gi-coupled GPCR (Ro1) in osteoblasts in vivo. Skeletal phenotypes were assessed in mice expressing Ro1 from conception, from late stages of embryogenesis, and after weaning. Long bones were assessed histologically and by microcomputed tomography. Expression of Ro1 from conception resulted in neonatal lethality that was associated with reduced bone mineralization. Expression of Ro1 starting at late embryogenesis resulted in a severe trabecular bone deficit at 12 wk of age (>51% reduction in trabecular bone volume fraction in the proximal tibia compared with sex-matched control littermates; n = 11; P < 0.01). Ro1 expression for 8 wk beginning at 4 wk of age resulted in a more than 20% reduction in trabecular bone volume fraction compared with sex-matched control littermates (n = 16; P < 0.01). Bone histomorphometry revealed that Ro1 expression is associated with reduced rates of bone formation and mineral apposition without a significant change in osteoblast or osteoclast surface. Our results indicate that signaling by a Gi-coupled GPCR in osteoblasts leads to osteopenia resulting from a reduction in trabecular bone formation. The severity of the phenotype is related to the timing and duration of Ro1 expression during growth and development. The skeletal phenotype in Ro1 mice bears some similarity to that produced by knockout of Gs-α expression in osteoblasts and thus may be due at least in part to Gi-mediated inhibition of adenylyl cyclase.
Keyword Designed G(i)-Coupled Receptor
Synthetic Ligands Rassl
Hormone-Related Peptide
Transgenic Mice
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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