Download PDF
Horm Metab Res 2016; 48(11): 689-699
DOI: 10.1055/s-0042-116156
Review
© Georg Thieme Verlag KG Stuttgart · New York

Gs/Gi Regulation of Bone Cell Differentiation: Review and Insights from Engineered Receptors

E. C. Hsiao
1   Division of Endocrinology and Metabolism and the Institute for Human Genetics, Department of Medicine, University of California, San Francisco, CA, USA
,
S. M. Millard
2   The University of Queensland-Mater Research Institute, Translational Research Institute, Kent Street, Woolloongabba, QLD, Australia
,
R. A. Nissenson
3   Endocrine Research Unit, VA Medical Center, and Departments of Medicine and Physiology, University of California, San Francisco, CA
4   Department of Medicine, University of California, San Francisco, CA, USA
› Author Affiliations
Further Information

Publication History

received 03 May 2016

accepted 17 August 2016

Publication Date:
19 September 2016 (online)

Also available at
    Permissions and Reprints

Abstract

G-protein coupled receptors (GPCRs) and their ligands are critical for normal osteoblast formation and function. GPCRs mediate a wide variety of biological processes and are activated by multiple types of extracellular signals, ranging from photons to small molecules to peptides. GPCRs signal through a select number of canonical pathways: the Gs and Gi pathways increase or decrease intracellular cAMP levels, respectively, by acting on adenylate cyclase, while the Gq pathway increases intracellular calcium by activating phospholipase C. In addition, non-canonical GPCR pathways such as β-arrestin activation are important for osteoblast function. Since many cells express multiple GPCRs, and each individual GPCR may activate multiple signaling pathways, the resulting combinatorial signal provides a mechanism for regulating complex biological processes and effector functions. However, the wide variety of GPCRs, the possibility of multiple receptors acting with signaling redundancy, and the possibility of an individual GPCR activating multiple signaling pathways, also pose challenges for elucidating the role of a particular GPCR. Here, we briefly review the roles of Gs and Gi GPCR signaling in osteoblast function. We describe the successful application of a strategy for directly manipulating the Gs and Gi pathways using engineered receptors. These powerful tools will allow further elucidation of the roles of GPCR signaling in specific lineages of osteoblastic cells, as well as in non-osteoblast cells, all of which remain critical areas of active research.

Key words

osteoblast - stem cells - G-protein coupled receptor - engineered receptor
 

  • References

  • 1 Aubin JE, Lian JB, Stein GS. Bone Formation: Maturation and Functional Activities of Osteoblast Lineage Cells. In: Favus MJ. (ed.). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, D.C.: American Society for Bone and Mineral Research; 2006: 20-29
    Google Scholar
  • 2 Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 2003; 63: 1256-1272
    CrossrefPubMedGoogle Scholar
  • 3 Karchin R, Karplus K, Haussler D. Classifying G-protein coupled receptors with support vector machines. Bioinformatics (Oxford, England) 2002; 18: 147-159
    CrossrefPubMedGoogle Scholar
  • 4 Brink CB, Harvey BH, Bodenstein J, Venter DP, Oliver DW. Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology. Br J Clin Pharmacol 2004; 57: 373-387
    CrossrefPubMedGoogle Scholar
  • 5 Gether U. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr Rev 2000; 21: 90-113
    CrossrefPubMedGoogle Scholar
  • 6 Bliziotes M, Murtagh J, Wiren K. Beta-adrenergic receptor kinase-like activity and beta-arrestin are expressed in osteoblastic cells. J Bone Miner Res 1996; 11: 820-826
    PubMedGoogle Scholar
  • 7 Ferrari SL, Pierroz DD, Glatt V, Goddard DS, Bianchi EN, Lin FT, Manen D, Bouxsein ML. Bone response to intermittent parathyroid hormone is altered in mice null for {beta}-Arrestin2. Endocrinology 2005; 146: 1854-1862
    CrossrefPubMedGoogle Scholar
  • 8 Spurney RF. Regulated expression of G protein-coupled receptor kinases (GRK’s) and beta-arrestins in osteoblasts. Calcif Tissue Int 2003; 73: 153-160
    CrossrefPubMedGoogle Scholar
  • 9 Wu M, Deng L, Zhu G, Li YP. G Protein and its signaling pathway in bone development and disease. Front Biosci 2010; 15: 957-985
    CrossrefPubMedGoogle Scholar
  • 10 Remoli C, Michienzi S, Sacchetti B, Consiglio AD, Cersosimo S, Spica E, Robey PG, Holmbeck K, Cumano A, Boyde A, Davis G, Saggio I, Riminucci M, Bianco P. Osteoblast-specific expression of the fibrous dysplasia (FD)-causing mutation Gsalpha(R201C) produces a high bone mass phenotype but does not reproduce FD in the mouse. J Bone Miner Res 2015; 30: 1030-1043
    CrossrefPubMedGoogle Scholar
  • 11 Saggio I, Remoli C, Spica E, Cersosimo S, Sacchetti B, Robey PG, Holmbeck K, Cumano A, Boyde A, Bianco P, Riminucci M. Constitutive expression of Gsalpha(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history. J Bone Miner Res 2014; 29: 2357-2368
    CrossrefPubMedGoogle Scholar
  • 12 Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, Forsayeth JR, Guettier JM, Chang WC, Pei Y, McCarthy KD, Nissenson RA, Wess J, Bockaert J, Roth BL. Engineering GPCR signaling pathways with RASSLs. Nat Meth 2008; 5: 673-678
    CrossrefPubMedGoogle Scholar
  • 13 Kronenberg HM. Gs signaling in osteoblasts and hematopoietic stem cells. Ann N Y Acad Sci 2010; 1192: 327-329
    CrossrefPubMedGoogle Scholar
  • 14 Bowler WB, Gallagher JA, Bilbe G. G-protein coupled receptors in bone. Front Biosci 1998; 3: d769-d780
    CrossrefPubMedGoogle Scholar
  • 15 Weinstein LS, Liu J, Sakamoto A, Xie T, Chen M. Minireview: GNAS: normal and abnormal functions. Endocrinology 2004; 145: 5459-5464
    CrossrefPubMedGoogle Scholar
  • 16 Weinstein LS, Shenker A. G protein mutations in human disease. Clin Biochem 1993; 26: 333-338
    CrossrefPubMedGoogle Scholar
  • 17 Weinstein LS, Yu S, Warner DR, Liu J. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 2001; 22: 675-705
    CrossrefPubMedGoogle Scholar
  • 18 Weinstein LS. G(s)alpha Mutations in Fibrous Dysplasia and McCune-Albright Syndrome. J Bone Miner Res 2006; 21 (Suppl. 02) P120-P124
    CrossrefPubMedGoogle Scholar
  • 19 Levine MA. Clinical implications of genetic defects in G proteins: oncogenic mutations in G alpha s as the molecular basis for the McCune-Albright syndrome. Arch Med Res 1999; 30: 522-531
    CrossrefPubMedGoogle Scholar
  • 20 Bianco P, Kuznetsov SA, Riminucci M, Fisher LW, Spiegel AM, Robey PG. Reproduction of human fibrous dysplasia of bone in immunocompromised mice by transplanted mosaics of normal and Gsalpha-mutated skeletal progenitor cells. J Clin Invest 1998; 101: 1737-1744
    CrossrefPubMedGoogle Scholar
  • 21 Germain-Lee EL, Schwindinger W, Crane JL, Zewdu R, Zweifel LS, Wand G, Huso DL, Saji M, Ringel MD, Levine MA. A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology 2005; 146: 4697-4709
    CrossrefPubMedGoogle Scholar
  • 22 Sakamoto A, Chen M, Kobayashi T, Kronenberg HM, Weinstein LS. Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation. J Bone Miner Res 2005; 20: 663-671
    PubMedGoogle Scholar
  • 23 Wu JY, Aarnisalo P, Bastepe M, Sinha P, Fulzele K, Selig MK, Chen M, Poulton IJ, Purton LE, Sims NA, Weinstein LS, Kronenberg HM. Gsalpha enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice. J Clin Invest 2011; 121: 3492-3504
    Google Scholar
  • 24 Sinha P, Aarnisalo P, Chubb R, Ono N, Fulzele K, Selig M, Saeed H, Chen M, Weinstein LS, Pajevic PD, Kronenberg HM, Wu JY. Loss of Gsalpha early in the osteoblast lineage favors adipogenic differentiation of mesenchymal progenitors and committed osteoblast precursors. J Bone Miner Res 2014; 29: 2414-2426
    CrossrefPubMedGoogle Scholar
  • 25 Fulzele K, Krause DS, Panaroni C, Saini V, Barry KJ, Liu X, Lotinun S, Baron R, Bonewald L, Feng JQ, Chen M, Weinstein LS, Wu JY, Kronenberg HM, Scadden DT, Divieti Pajevic P. Myelopoiesis is regulated by osteocytes through Gsalpha-dependent signaling. Blood 2013; 121: 930-939
    CrossrefPubMedGoogle Scholar
  • 26 Wu JY, Purton LE, Rodda SJ, Chen M, Weinstein LS, McMahon AP, Scadden DT, Kronenberg HM. Osteoblastic regulation of B lymphopoiesis is mediated by Gs{alpha}-dependent signaling pathways. Proc Natl Acad Sci U S A 2008; 105: 16976-16981
    CrossrefPubMedGoogle Scholar
  • 27 Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen A, Nackers L, Lorenzo J, Shen L, Weinstein L. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci USA 2005; 102: 7386-7391
    CrossrefPubMedGoogle Scholar
  • 28 Weinstein L, Xie T, Zhang Q, Chen M. Studies of the regulation and function of the Gs alpha gene Gnas using gene targeting technology. Pharmacol Ther 2007; 115: 271-291
    CrossrefPubMedGoogle Scholar
  • 29 Blomstrand S, Claësson I, Säve-Söderbergh J. A case of lethal congenital dwarfism with accelerated skeletal maturation. Pediatr Radiol 1985; 15: 141-143
    CrossrefPubMedGoogle Scholar
  • 30 Jobert A, Zhang P, Couvineau A, Bonaventure J, Roume J, Le Merrer M, Silve C. Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J clin Invest 1998; 102: 34-40
    CrossrefPubMedGoogle Scholar
  • 31 Lanske B, Amling M, Neff L, Guiducci J, Baron R, Kronenberg H. Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development. J Clin Invest 1999; 104: 399-407
    CrossrefPubMedGoogle Scholar
  • 32 Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Develop 1994; 8: 277-289
    CrossrefPubMedGoogle Scholar
  • 33 Miao D, He B, Karaplis AC, Goltzman D. Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest 2002; 109: 1173-1182
    CrossrefPubMedGoogle Scholar
  • 34 Hirai T, Chagin AS, Kobayashi T, Mackem S, Kronenberg HM. Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life. Proc Natl Acad Sci USA 2011; 108: 191-196
    CrossrefPubMedGoogle Scholar
  • 35 Motomura K, Ohtsuru A, Enomoto H, Tsukazaki T, Namba H, Tsuji Y, Yamashita S. Osteogenic action of parathyroid hormone-related peptide (1-141) in rat ROS cells. Endocr J 1996; 43: 527-535
    CrossrefPubMedGoogle Scholar
  • 36 Brommage R, Hotchkiss C, Lees C, Stancill M, Hock J, Jerome C. Daily treatment with human recombinant parathyroid hormone-(1-34), LY333334, for 1 year increases bone mass in ovariectomized monkeys. J Clin Endocrinol Metab 1999; 84: 3757-3763
    PubMedGoogle Scholar
  • 37 Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997; 138: 4607-4612
    CrossrefPubMedGoogle Scholar
  • 38 Armamento-Villareal R, Ziambaras K, Abbasi-Jarhomi SH, Dimarogonas A, Halstead L, Fausto A, Avioli LV, Civitelli R. An intact N terminus is required for the anabolic action of parathyroid hormone on adult female rats. J Bone Miner Res 1997; 12: 384-392
    CrossrefPubMedGoogle Scholar
  • 39 Whitfield JF, Morley P, Willick GE, Ross V, Barbier JR, Isaacs RJ, Ohannessian-Barry L. Stimulation of the growth of femoral trabecular bone in ovariectomized rats by the novel parathyroid hormone fragment, hPTH-(1-31)NH2 (Ostabolin). Calcif Tissue Int 1996; 58: 81-87
    CrossrefPubMedGoogle Scholar
  • 40 Alkhiary YM, Gerstenfeld LC, Krall E, Westmore M, Sato M, Mitlak BH, Einhorn TA. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg 2005; 87: 731-741
    CrossrefPubMedGoogle Scholar
  • 41 Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 1999; 14: 960-968
    CrossrefPubMedGoogle Scholar
  • 42 Kuznetsov SA, Riminucci M, Ziran N, Tsutsui TW, Corsi A, Calvi L, Kronenberg HM, Schipani E, Robey PG, Bianco P. The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow. J Cell Biol 2004; 167: 1113-1122
    CrossrefPubMedGoogle Scholar
  • 43 Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 2007; 40: 1434-1446
    CrossrefPubMedGoogle Scholar
  • 44 Mosekilde L. Primary hyperparathyroidism and the skeleton. Clin Endocrinol (Oxf) 2008; 69: 1-19
    CrossrefPubMedGoogle Scholar
  • 45 Fu Q, Jilka RL, Manolagas SC, O’Brien CA. Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem 2002; 277: 48868-48875
    CrossrefPubMedGoogle Scholar
  • 46 Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, Chandrasekhar S, Martin TJ, Onyia JE. Catabolic effects of continuous human PTH (1--38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology 2001; 142: 4047-4054
    CrossrefPubMedGoogle Scholar
  • 47 Dean T, Vilardaga JP, Potts Jr. JT, Gardella TJ. Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. Mol Endocrinol (Baltimore, Md) 2008; 22: 156-166
    CrossrefPubMedGoogle Scholar
  • 48 Gardella TJ, Vilardaga JP. International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors – family B G protein-coupled receptors. Pharmacol Rev 2015; 67: 310-337
    CrossrefPubMedGoogle Scholar
  • 49 Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O’Brien CA, Manolagas SC, Jilka RL. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 2005; 146: 4577-4583
    CrossrefPubMedGoogle Scholar
  • 50 Guo J, Liu M, Yang D, Bouxsein ML, Saito H, Galvin RJ, Kuhstoss SA, Thomas CC, Schipani E, Baron R, Bringhurst FR, Kronenberg HM. Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab 2010; 11: 161-171
    CrossrefPubMedGoogle Scholar
  • 51 Kramer I, Loots GG, Studer A, Keller H, Kneissel M. Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res 2010; 25: 178-189
    CrossrefPubMedGoogle Scholar
  • 52 Graham S, Gamie Z, Polyzois I, Narvani AA, Tzafetta K, Tsiridis E, Helioti M, Mantalaris A. Prostaglandin EP2 and EP4 receptor agonists in bone formation and bone healing: In vivo and in vitro evidence. Expert Opin Investig Drugs 2009; 18: 746-766
    PubMedGoogle Scholar
  • 53 Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, Cho SG, Li C, Yi T, Wu X, Li XY, de Crombrugghe B, Hook M, Liu M. Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development 2009; 136: 2747-2756
    CrossrefPubMedGoogle Scholar
  • 54 Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G. Leptin regulates bone formation via the sympathetic nervous system. Cell 2002; 111: 305-317
    CrossrefPubMedGoogle Scholar
  • 55 Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 2005; 434: 514-520
    CrossrefPubMedGoogle Scholar
  • 56 Bonnet N, Pierroz DD, Ferrari SL. Adrenergic control of bone remodeling and its implications for the treatment of osteoporosis. J Musculoskelet Neuronal Interact 2008; 8: 94-104
    PubMedGoogle Scholar
  • 57 Romero G, Sneddon WB, Yang Y, Wheeler D, Blair HC, Friedman PA. Parathyroid hormone receptor directly interacts with dishevelled to regulate beta-Catenin signaling and osteoclastogenesis. J Biol Chem 2010; 285: 14756-14763
    CrossrefPubMedGoogle Scholar
  • 58 Sneddon WB, Friedman PA. Beta-arrestin-dependent parathyroid hormone-stimulated extracellular signal-regulated kinase activation and parathyroid hormone type 1 receptor internalization. Endocrinology 2007; 148: 4073-4079
    CrossrefPubMedGoogle Scholar
  • 59 Sneddon WB, Magyar CE, Willick GE, Syme CA, Galbiati F, Bisello A, Friedman PA. Ligand-selective dissociation of activation and internalization of the parathyroid hormone (PTH) receptor: conditional efficacy of PTH peptide fragments. Endocrinology 2004; 145: 2815-2823
    CrossrefPubMedGoogle Scholar
  • 60 Sneddon WB, Syme CA, Bisello A, Magyar CE, Rochdi MD, Parent JL, Weinman EJ, Abou-Samra AB, Friedman PA. Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50). J Biol Chem 2003; 278: 43787-43796
    CrossrefPubMedGoogle Scholar
  • 61 Sneddon WB, Yang Y, Ba J, Harinstein LM, Friedman PA. Extracellular signal-regulated kinase activation by parathyroid hormone in distal tubule cells. Am J Physiol Renal Physiol 2007; 292: F1028-F1034
    PubMedGoogle Scholar
  • 62 Regard JB, Zhong Z, Williams BO, Yang Y. Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harbor Perspect Biol. 2012; 4 pii: a007997 DOI: 10.1101/cshperspect.a007997.
    PubMedGoogle Scholar
  • 63 Malbon CC. G proteins in development. Nat Rev Mol Cell Biol 2005; 6: 689-701
    CrossrefPubMedGoogle Scholar
  • 64 Katritch V, Cherezov V, Stevens RC. Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol 2013; 53: 531-556
    CrossrefPubMedGoogle Scholar
  • 65 Birnbaumer L. Expansion of signal transduction by G proteins. The second 15 years or so: from 3 to 16 alpha subunits plus betagamma dimers. Biochim Biophys Acta 2007; 1768: 772-793
    CrossrefPubMedGoogle Scholar
  • 66 Dziak R, Yang BM, Leung BW, Li S, Marzec N, Margarone J, Bobek L. Effects of sphingosine-1-phosphate and lysophosphatidic acid on human osteoblastic cells. Prostaglandins Leukot Essent Fatty Acids 2003; 68: 239-249
    CrossrefPubMedGoogle Scholar
  • 67 Grey A, Banovic T, Naot D, Hill B, Callon K, Reid I, Cornish J. Lysophosphatidic acid is an osteoblast mitogen whose proliferative actions involve G(i) proteins and protein kinase C, but not P42/44 mitogen-activated protein kinases. Endocrinology 2001; 142: 1098-1106
    CrossrefPubMedGoogle Scholar
  • 68 Grey A, Chen Q, Callon K, Xu X, Reid IR, Cornish J. The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase. Endocrinology 2002; 143: 4755-4763
    CrossrefPubMedGoogle Scholar
  • 69 Lyons JM, Karin NJ. A role for G protein-coupled lysophospholipid receptors in sphingolipid-induced Ca2+ signaling in MC3T3-E1 osteoblastic cells. J Bone Miner Res 2001; 16: 2035-2042
    CrossrefPubMedGoogle Scholar
  • 70 Rosen H, Gonzalez-Cabrera PJ, Sanna MG, Brown S. Sphingosine 1-phosphate receptor signaling. Annu Rev Biochem 2009; 78: 743-768
    CrossrefPubMedGoogle Scholar
  • 71 Kong Y, Wang H, Lin T, Wang S. Sphingosine-1-phosphate/S1P receptors signaling modulates cell migration in human bone marrow-derived mesenchymal stem cells. Mediators Inflamm 2014; 565369
    PubMedGoogle Scholar
  • 72 Quint P, Ruan M, Pederson L, Kassem M, Westendorf JJ, Khosla S, Oursler MJ. Sphingosine 1-phosphate (S1P) receptors 1 and 2 coordinately induce mesenchymal cell migration through S1P activation of complementary kinase pathways. J Biol Chem 2013; 288: 5398-5406
    CrossrefPubMedGoogle Scholar
  • 73 Liu YB, Kharode Y, Bodine PV, Yaworsky PJ, Robinson JA, Billiard J. LPA induces osteoblast differentiation through interplay of two receptors: LPA1 and LPA4. J Cell Biochem 2010; 109: 794-800
    PubMedGoogle Scholar
  • 74 Panupinthu N, Zhao L, Possmayer F, Ke HZ, Sims SM, Dixon SJ. P2×7 nucleotide receptors mediate blebbing in osteoblasts through a pathway involving lysophosphatidic acid. J Biol Chem 2007; 282: 3403-3412
    CrossrefPubMedGoogle Scholar
  • 75 Gennero I, Laurencin-Dalicieux S, Conte-Auriol F, Briand-Mesange F, Laurencin D, Rue J, Beton N, Malet N, Mus M, Tokumura A, Bourin P, Vico L, Brunel G, Oreffo RO, Chun J, Salles JP. Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass. Bone 2011; 49: 395-403
    CrossrefPubMedGoogle Scholar
  • 76 Hosoya M, Kawamata Y, Fukusumi S, Fujii R, Habata Y, Hinuma S, Kitada C, Honda S, Kurokawa T, Onda H, Nishimura O, Fujino M. Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem 2000; 275: 21061-21067
    CrossrefPubMedGoogle Scholar
  • 77 Xie H, Tang SY, Cui RR, Huang J, Ren XH, Yuan LQ, Lu Y, Yang M, Zhou HD, Wu XP, Luo XH, Liao EY. Apelin and its receptor are expressed in human osteoblasts. Regul Pept 2006; 134: 118-125
    CrossrefPubMedGoogle Scholar
  • 78 Xie H, Yuan LQ, Luo XH, Huang J, Cui RR, Guo LJ, Zhou HD, Wu XP, Liao EY. Apelin suppresses apoptosis of human osteoblasts. Apoptosis 2007; 12: 247-254
    CrossrefPubMedGoogle Scholar
  • 79 Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci USA 2006; 103: 696-701
    CrossrefPubMedGoogle Scholar
  • 80 Lau KH, Baylink DJ. Molecular mechanism of action of fluoride on bone cells. J Bone Miner Res 1998; 13: 1660-1667
    CrossrefPubMedGoogle Scholar
  • 81 Wang N, Robaye B, Agrawal A, Skerry TM, Boeynaems JM, Gartland A. Reduced bone turnover in mice lacking the P2Y13 receptor of ADP. Mol Endocrinol 2012; 26: 142-152
    CrossrefPubMedGoogle Scholar
  • 82 Wang N, Rumney RM, Yang L, Robaye B, Boeynaems JM, Skerry TM, Gartland A. The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading. J Bone Miner Res 2013; 28: 1446-1456
    CrossrefPubMedGoogle Scholar
  • 83 Wattanachanya L, Wang L, Millard SM, Lu WD, O’Carroll D, Hsiao EC, Conklin BR, Nissenson RA. Assessing the osteoblast transcriptome in a model of enhanced bone formation due to constitutive G-G protein signaling in osteoblasts. Exp Cell Res 2015; 333: 289-302
    CrossrefPubMedGoogle Scholar
  • 84 Wattanachanya L, Lu WD, Kundu RK, Wang L, Abbott MJ, O’Carroll D, Quertermous T, Nissenson RA. Increased bone mass in mice lacking the adipokine apelin. Endocrinology 2013; 154: 2069-2080
    CrossrefPubMedGoogle Scholar
  • 85 Ford J, Hajibeigi A, Long M, Hahner L, Gore C, Hsieh JT, Clegg D, Zerwekh J, Oz OK. GPR30 deficiency causes increased bone mass, mineralization, and growth plate proliferative activity in male mice. J Bone Miner Res 2011; 26: 298-307
    CrossrefPubMedGoogle Scholar
  • 86 Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schutz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008; 135: 825-837
    CrossrefPubMedGoogle Scholar
  • 87 Lundberg P, Allison SJ, Lee NJ, Baldock PA, Brouard N, Rost S, Enriquez RF, Sainsbury A, Lamghari M, Simmons P, Eisman JA, Gardiner EM, Herzog H. Greater bone formation of Y2 knockout mice is associated with increased osteoprogenitor numbers and altered Y1 receptor expression. J Biol Chem 2007; 282: 19082-19091
    CrossrefPubMedGoogle Scholar
  • 88 Baldock PA, Allison SJ, Lundberg P, Lee NJ, Slack K, Lin EJ, Enriquez RF, McDonald MM, Zhang L, During MJ, Little DG, Eisman JA, Gardiner EM, Yulyaningsih E, Lin S, Sainsbury A, Herzog H. Novel role of Y1 receptors in the coordinated regulation of bone and energy homeostasis. J Biol Chem 2007; 282: 19092-19102
    CrossrefPubMedGoogle Scholar
  • 89 Lee NJ, Nguyen AD, Enriquez RF, Doyle KL, Sainsbury A, Baldock PA, Herzog H. Osteoblast specific Y1 receptor deletion enhances bone mass. Bone 2011; 48: 461-467
    CrossrefPubMedGoogle Scholar
  • 90 Sousa DM, Baldock PA, Enriquez RF, Zhang L, Sainsbury A, Lamghari M, Herzog H, Neuropeptide Y. Y1 receptor antagonism increases bone mass in mice. Bone 2012; 51: 8-16
    CrossrefPubMedGoogle Scholar
  • 91 Schipani E, Kruse K, Juppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 1995; 268: 98-100
    CrossrefPubMedGoogle Scholar
  • 92 Calvi LM, Sims NA, Hunzelman JL, Knight MC, Giovannetti A, Saxton JM, Kronenberg HM, Baron R, Schipani E. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest 2001; 107: 277-286
    CrossrefPubMedGoogle Scholar
  • 93 Guo J, Chung UI, Kondo H, Bringhurst FR, Kronenberg HM. The PTH/PTHrP receptor can delay chondrocyte hypertrophy in vivo without activating phospholipase C. Dev Cell 2002; 3: 183-194
    CrossrefPubMedGoogle Scholar
  • 94 Rhee Y, Allen MR, Condon K, Lezcano V, Ronda AC, Galli C, Olivos N, Passeri G, O’Brien CA, Bivi N, Plotkin LI, Bellido T. PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling. J Bone Miner Res 2011; 26: 1035-1046
    CrossrefPubMedGoogle Scholar
  • 95 Pioszak AA, Harikumar KG, Parker NR, Miller LJ, Xu HE. Dimeric arrangement of the parathyroid hormone receptor and a structural mechanism for ligand-induced dissociation. J Biol Chem 2010; 285: 12435-12444
    CrossrefPubMedGoogle Scholar
  • 96 Coward P, Wada HG, Falk MS, Chan SD, Meng F, Akil H, Conklin BR. Controlling signaling with a specifically designed Gi-coupled receptor. Proc Natl Acad Sci USA 1998; 95: 352-357
    CrossrefPubMedGoogle Scholar
  • 97 Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci USA 2007; 104: 5163-5168
    CrossrefPubMedGoogle Scholar
  • 98 Redfern CH, Coward P, Degtyarev MY, Lee EK, Kwa AT, Hennighausen L, Bujard H, Fishman GI, Conklin BR. Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice. Nat Biotechnol 1999; 17: 165-169
    CrossrefPubMedGoogle Scholar
  • 99 Scearce-Levie K, Lieberman MD, Elliott HH, Conklin BR. Engineered G protein coupled receptors reveal independent regulation of internalization, desensitization and acute signaling. BMC Biol 2005; 3: 3
    CrossrefPubMedGoogle Scholar
  • 100 Sweger EJ, Casper KB, Scearce-Levie K, Conklin BR, McCarthy KD. Development of hydrocephalus in mice expressing the G(i)-coupled GPCR Ro1 RASSL receptor in astrocytes. J Neurosci 2007; 27: 2309-2317
    CrossrefPubMedGoogle Scholar
  • 101 Zhao GQ, Zhang Y, Hoon MA, Chandrashekar J, Erlenbach I, Ryba NJ, Zuker CS. The receptors for mammalian sweet and umami taste. Cell 2003; 115: 255-266
    CrossrefPubMedGoogle Scholar
  • 102 Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J, Yu GQ, Adame A, Devidze N, Dubal DB, Masliah E, Conklin BR, Mucke L. Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci 2015; 18: 423-434
    CrossrefPubMedGoogle Scholar
  • 103 Lopez AJ, Kramar E, Matheos DP, White AO, Kwapis J, Vogel-Ciernia A, Sakata K, Espinoza M, Wood MA. Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation. J Neurosci 2016; 36: 3588-3599
    CrossrefPubMedGoogle Scholar
  • 104 Nation HL, Nicoleau M, Kinsman BJ, Browning KN, Stocker SD. DREADD-induced Activation of Subfornical Organ Neurons Stimulates Thirst and Salt Appetite. J Neurophysiol 2016; 115: 3123-3129
    CrossrefPubMedGoogle Scholar
  • 105 Siuda ER, Al-Hasani R, McCall JG, Bhatti DL, Bruchas MR. Chemogenetic and Optogenetic Activation of Galphas Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States. Neuropsychopharmacology 2016; DOI: 10.1038/npp.2015.371.
    PubMedGoogle Scholar
  • 106 Roth BL. DREADDs for Neuroscientists. Neuron 2016; 89: 683-694
    CrossrefPubMedGoogle Scholar
  • 107 Akil O, Hall-Glenn F, Chang J, Li A, Chang W, Lustig LR, Alliston T, Hsiao EC. Disrupted bone remodeling leads to cochlear overgrowth and hearing loss in a mouse model of fibrous dysplasia. PloS One 2014; 9: e94989
    CrossrefPubMedGoogle Scholar
  • 108 Hsiao EC, Boudignon BM, Chang WC, Bencsik M, Peng J, Nguyen TD, Manalac C, Halloran BP, Conklin BR, Nissenson RA. Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass. Proc Natl Acad Sci U S A 2008; 105: 1209-1214
    CrossrefPubMedGoogle Scholar
  • 109 Hsiao EC, Boudignon BM, Halloran BP, Nissenson RA, Conklin BR. G(s) G protein-coupled receptor signaling in osteoblasts elicits age-dependent effects on bone formation. J Bone Miner Res 2010; 25: 584-593
    CrossrefPubMedGoogle Scholar
  • 110 Hsiao EC, Millard SM, Louie A, Huang Y, Conklin BR, Nissenson RA. Ligand-mediated activation of an engineered gs g protein-coupled receptor in osteoblasts increases trabecular bone formation. Mol Endocrinol 2010; 24: 621-631
    CrossrefPubMedGoogle Scholar
  • 111 Hsiao EC, Nguyen TD, Ng JK, Scott MJ, Chang WC, Zahed H, Conklin BR. Constitutive Gs activation using a single-construct tetracycline-inducible expression system in embryonic stem cells and mice. Stem Cell Res Ther 2011; 2: 11
    CrossrefPubMedGoogle Scholar
  • 112 Kazakia GJ, Speer D, Shanbhag S, Majumdar S, Conklin BR, Nissenson RA, Hsiao EC. Mineral Composition is Altered by Osteoblast Expression of an Engineered G(s)-Coupled Receptor. Calcif Tissue Int 2011; 89: 10-20
    CrossrefPubMedGoogle Scholar
  • 113 Schepers K, Hsiao EC, Garg T, Scott MJ, Passegue E. Activated Gs signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice. Blood 2012; 120: 3425-3435
    CrossrefPubMedGoogle Scholar
  • 114 Wang L, Hsiao EC, Lieu S, Scott M, O’Carroll D, Urrutia A, Conklin BR, Colnot C, Nissenson RA. Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing. J Bone Miner Res 2015; 30: 1896-1904
    CrossrefPubMedGoogle Scholar
  • 115 Chang WC, Ng JK, Nguyen T, Pellissier L, Claeysen S, Hsiao EC, Conklin BR. Modifying ligand-induced and constitutive signaling of the human 5-HT4 receptor. PLoS One 2007; 2: e1317
    CrossrefPubMedGoogle Scholar
  • 116 Anastasilakis AD, Savvides M, Polyzos SA, Georgopoulos C, Delaroudis S. Normochromic normocytic anemia in a postmenopausal woman with severe osteoporosis treated with intermittent parathyroid hormone. J Bone Miner Metab 2010; 28: 108-110
    CrossrefPubMedGoogle Scholar
  • 117 Trunzo JA, McHenry CR, Schulak JA, Wilhelm SM. Effect of parathyroidectomy on anemia and erythropoietin dosing in end-stage renal disease patients with hyperparathyroidism. Surgery 2008; 144: 915-918 discussion 919
    CrossrefPubMedGoogle Scholar
  • 118 Cain CJ, Valencia JT, Ho S, Jordan K, Mattingly A, Morales BM, Hsiao EC. Increased Gs Signaling in Osteoblasts Reduces Bone Marrow and Whole-Body Adiposity in Male Mice. Endocrinology 2016; 157: 1481-1494
    CrossrefPubMedGoogle Scholar
  • 119 Peng J, Bencsik M, Louie A, Lu W, Millard S, Nguyen P, Burghardt A, Majumdar S, Wronski TJ, Halloran B, Conklin BR, Nissenson RA. Conditional expression of a Gi-coupled receptor in osteoblasts results in trabecular osteopenia. Endocrinology 2008; 149: 1329-1337
    CrossrefPubMedGoogle Scholar
  • 120 Millard SM, Louie AM, Wattanachanya L, Wronski TJ, Conklin BR, Nissenson RA. Blockade of receptor-activated G(i) signaling in osteoblasts in vivo leads to site-specific increases in cortical and cancellous bone formation. J Bone Miner Res 2011; 26: 822-832
    CrossrefPubMedGoogle Scholar