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.
Hsiao
Edward C
EC
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. ehsiao@gladstone.ucsf.edu
Boudignon
Benjamin M
BM
Chang
Wei C
WC
Bencsik
Margaret
M
Peng
Jeffrey
J
Nguyen
Trieu D
TD
Manalac
Carlota
C
Halloran
Bernard P
BP
Conklin
Bruce R
BR
Nissenson
Robert A
RA
D000595:Amino Acid Sequence; D000818:Animals; D015519:Bone Density / Q000502:physiology*; D002460:Cell Line; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000737:chemistry* / Q000378:metabolism*; D015202:Protein Engineering / Q000379:methods; D044422:Receptors, Serotonin, 5-HT4 / Q000096:biosynthesis* / Q000235:genetics*; D058828:Serotonin 5-HT4 Receptor Agonists; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D008024:Ligands; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D019205:GTP-Binding Protein alpha Subunits, Gs