Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass
- Edward C. Hsiao†,‡,§,
- Benjamin M. Boudignon¶,
- Wei C. Chang†,‖,
- Margaret Bencsik¶,
- Jeffrey Peng¶,
- Trieu D. Nguyen†,
- Carlota Manalac†,
- Bernard P. Halloran‡,¶,
- Bruce R. Conklin†,‡,††,§, and
- Robert A. Nissenson‡,¶,§
- †Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158;
- ‡Department of Medicine, University of California, San Francisco, CA 94143;
- ¶Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA 94121;
- ‖Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, CA 94158; and
- ††Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158
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Edited by Kathryn V. Anderson, Sloan–Kettering Institute, New York, NY, and approved November 28, 2007 (received for review August 7, 2007)
Abstract
Osteoblasts are essential for maintaining bone mass, avoiding osteoporosis, and repairing injured bone. Activation of osteoblast G protein-coupled receptors (GPCRs), such as the parathyroid hormone receptor, can increase bone mass; however, the anabolic mechanisms are poorly understood. Here we use “Rs1,” an engineered GPCR with constitutive Gs signaling, to evaluate the temporal and skeletal effects of Gs signaling in murine osteoblasts. In vivo, Rs1 expression induces a dramatic anabolic skeletal response, with midfemur girth increasing 1,200% and femur mass increasing 380% in 9-week-old mice. Bone volume, cellularity, areal bone mineral density, osteoblast gene markers, and serum bone turnover markers were also elevated. No such phenotype developed when Rs1 was expressed after the first 4 weeks of postnatal life, indicating an exquisite temporal sensitivity of osteoblasts to Rs1 expression. This pathway may represent an important determinant of bone mass and may open future avenues for enhancing bone repair and treating metabolic bone diseases.
Footnotes
- §To whom correspondence may be addressed. E-mail: ehsiao{at}gladstone.ucsf.edu, bconklin{at}gladstone.ucsf.edu, or robert.nissenson{at}va.gov
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Author contributions: E.C.H., B.M.B., W.C.C., B.P.H., B.R.C., and R.A.N. designed research; E.C.H., B.M.B., W.C.C., M.B., J.P., T.D.N., C.M., B.P.H., B.R.C., and R.A.N. performed research; M.B. contributed new reagents/analytic tools; E.C.H., B.M.B., W.C.C., B.P.H., B.R.C., and R.A.N. analyzed data; and E.C.H., B.R.C., and R.A.N. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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Data deposition: The mouse strains reported in this paper have been deposited in the Mutant Mouse Regional Resource Centers (MMRRC) database [accession nos. 029992 FVB/N-Tg(TetO-HTR4*D100A) (TetO-Rs1-line G) and 029993 FVB/N-Tg(TetO-HTR4*D100A) (TetO-Rs1-line B)]. The plasmids reported in this paper have been deposited in the Addgene database [accession nos. 16313 (pUHG10.3 TetO-Rs1) and 16312 (pUNIV-SIG-5HT4D100A)].
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This article contains supporting information online at www.pnas.org/cgi/content/full/0707457105/DC1.
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Freely available online through the PNAS open access option.
- © 2008 by The National Academy of Sciences of the USA
