Ligand-mediated activation of an engineered Gs G protein-coupled receptor in osteoblasts increases trabecular bone formation

Hsiao, Edward C., Millard, Susan M., Louie, Alyssa, Huang, Yong, Conklin, Bruce R. and Nissenson, Robert A. (2010) Ligand-mediated activation of an engineered Gs G protein-coupled receptor in osteoblasts increases trabecular bone formation. Molecular Endocrinology, 24 3: 621-631. doi:10.1210/me.2009-0424


Author Hsiao, Edward C.
Millard, Susan M.
Louie, Alyssa
Huang, Yong
Conklin, Bruce R.
Nissenson, Robert A.
Title Ligand-mediated activation of an engineered Gs G protein-coupled receptor in osteoblasts increases trabecular bone formation
Formatted title
Ligand-mediated activation of an engineered Gs G protein-coupled receptor in osteoblasts increases trabecular bone formation

Journal name Molecular Endocrinology   Check publisher's open access policy
ISSN 0888-8809
1944-9917
Publication date 2010-03
Sub-type Article (original research)
DOI 10.1210/me.2009-0424
Volume 24
Issue 3
Start page 621
End page 631
Total pages 11
Place of publication Chevy Chase, MD, United States
Publisher The Endocrine Society
Language eng
Formatted abstract
Age-dependent changes in skeletal growth play important roles in regulating skeletal expansion and in the course of many diseases affecting bone. How G protein-coupled receptor (GPCR) signaling affects these changes is poorly understood. Previously, we described a mouse model expressing Rs1, an engineered receptor with constitutive Gs activity. Rs1 expression in osteoblasts from gestation induced a dramatic age-dependent increase in trabecular bone with features resembling fibrous dysplasia; however, these changes were greatly minimized if Rs1 expression was delayed until after puberty. To further investigate whether ligand-induced activation of the Gs-GPCR pathway affects bone formation in adult mice, we activated Rs1 in adult mice with the synthetic ligand RS67333 delivered continuously via an osmotic pump or intermittently by daily injections. We found that osteoblasts from adult animals can be stimulated to form large amounts of bone, indicating that adult mice are sensitive to the dramatic bone- forming actions of Gs signaling in osteoblasts. In addition, our results show that intermittent and continuous activation of Rs1 led to structurally similar but quantitatively different degrees of trabecular bone formation. These results indicate that activation of a Gs-coupled receptor in osteoblasts of adult animals by either intermittent or continuous ligand administration can increase trabecular bone formation. In addition, osteoblasts located at the bone epiphyses may be more responsive to Gs signaling than osteoblasts at the bone diaphysis. This model provides a powerful tool for investigating the effects of ligand-activated Gs-GPCR signaling on dynamic bone growth and remodeling.
Keyword Parathyroid-Hormone Fragment
Beta-Adrenergic-Receptors
Fibrous Dysplasia
Conditional Expression
Postmenopausal Women
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

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