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Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass.

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 G(s) signaling, to evaluate the temporal and skeletal effects of G(s) 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.

Pubmed ID: 18212126


  • Hsiao EC
  • Boudignon BM
  • Chang WC
  • Bencsik M
  • Peng J
  • Nguyen TD
  • Manalac C
  • Halloran BP
  • Conklin BR
  • Nissenson RA


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

January 29, 2008

Associated Grants

  • Agency: NIDDK NIH HHS, Id: 2T32DK07418-26
  • Agency: NIDDK NIH HHS, Id: DK072071
  • Agency: NIDDK NIH HHS, Id: R01 DK072071
  • Agency: NHLBI NIH HHS, Id: R01 HL60664-07
  • Agency: NCRR NIH HHS, Id: RR18928-01

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Bone Density
  • Cell Line
  • Female
  • GTP-Binding Protein alpha Subunits, Gs
  • Humans
  • Ligands
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Osteoblasts
  • Protein Engineering
  • Receptors, Serotonin, 5-HT4
  • Serotonin 5-HT4 Receptor Agonists
  • Signal Transduction