Control of Bone Mass and Remodeling by PTH Receptor Signaling in Osteocytes

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2008 Aug 14

PMID 18698360

Citations 192

Authors

Charles A OBrien

Lilian I Plotkin

Carlo Galli

Joseph J Goellner

Arancha R Gortazar

Matthew R Allen

Alexander G Robling

Mary Bouxsein

Ernestina Schipani

Charles H Turner

Robert L Jilka

Robert S Weinstein

Stavros C Manolagas

Teresita Bellido

Affiliations

Soon will be listed here.

Abstract

Osteocytes, former osteoblasts buried within bone, are thought to orchestrate skeletal adaptation to mechanical stimuli. However, it remains unknown whether hormones control skeletal homeostasis through actions on osteocytes. Parathyroid hormone (PTH) stimulates bone remodeling and may cause bone loss or bone gain depending on the balance between bone resorption and formation. Herein, we demonstrate that transgenic mice expressing a constitutively active PTH receptor exclusively in osteocytes exhibit increased bone mass and bone remodeling, as well as reduced expression of the osteocyte-derived Wnt antagonist sclerostin, increased Wnt signaling, increased osteoclast and osteoblast number, and decreased osteoblast apoptosis. Deletion of the Wnt co-receptor LDL related receptor 5 (LRP5) attenuates the high bone mass phenotype but not the increase in bone remodeling induced by the transgene. These findings demonstrate that PTH receptor signaling in osteocytes increases bone mass and the rate of bone remodeling through LRP5-dependent and -independent mechanisms, respectively.

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References

Jilka R, Takahashi K, Munshi M, Williams D, Roberson P, Manolagas S . Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption. J Clin Invest. 1998; 101(9):1942-50. PMC: 508781. DOI: 10.1172/JCI1039. View

Yochum G, McWeeney S, Rajaraman V, Cleland R, Peters S, Goodman R . Serial analysis of chromatin occupancy identifies beta-catenin target genes in colorectal carcinoma cells. Proc Natl Acad Sci U S A. 2007; 104(9):3324-9. PMC: 1805576. DOI: 10.1073/pnas.0611576104. View

Glass 2nd D, Karsenty G . In vivo analysis of Wnt signaling in bone. Endocrinology. 2007; 148(6):2630-4. DOI: 10.1210/en.2006-1372. View

Clement-Lacroix P, Ai M, Morvan F, Roman-Roman S, Vayssiere B, Belleville C . Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci U S A. 2005; 102(48):17406-11. PMC: 1297659. DOI: 10.1073/pnas.0505259102. View

Parfitt A, Drezner M, Glorieux F, Kanis J, MALLUCHE H, Meunier P . Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987; 2(6):595-610. DOI: 10.1002/jbmr.5650020617. View

Calvi L, Sims N, Hunzelman J, Knight M, Giovannetti A, Saxton J . Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest. 2001; 107(3):277-86. PMC: 199196. DOI: 10.1172/JCI11296. View

Gong Y, Slee R, Fukai N, Rawadi G, Roman-Roman S, Reginato A . LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001; 107(4):513-23. DOI: 10.1016/s0092-8674(01)00571-2. View

Robling A, Niziolek P, Baldridge L, Condon K, Allen M, Alam I . Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2007; 283(9):5866-75. DOI: 10.1074/jbc.M705092200. View

Parfitt A, Schipani E, Rao D, Kupin W, Han Z, Juppner H . Hypercalcemia due to constitutive activity of the parathyroid hormone (PTH)/PTH-related peptide receptor: comparison with primary hyperparathyroidism. J Clin Endocrinol Metab. 1996; 81(10):3584-8. DOI: 10.1210/jcem.81.10.8855805. View

10.

Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K . Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 2007; 5(6):464-75. DOI: 10.1016/j.cmet.2007.05.001. View

11.

Ueno Y, Shinki T, Nagai Y, Murayama H, Fujii K, Suda T . In vivo administration of 1,25-dihydroxyvitamin D3 suppresses the expression of RANKL mRNA in bone of thyroparathyroidectomized rats constantly infused with PTH. J Cell Biochem. 2003; 90(2):267-77. DOI: 10.1002/jcb.10623. View

12.

Miao D, Li J, Xue Y, Su H, Karaplis A, Goltzman D . Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice. Endocrinology. 2004; 145(8):3554-62. DOI: 10.1210/en.2003-1695. View

13.

Bouxsein M, Myers K, Shultz K, Donahue L, Rosen C, Beamer W . Ovariectomy-induced bone loss varies among inbred strains of mice. J Bone Miner Res. 2005; 20(7):1085-92. DOI: 10.1359/JBMR.050307. View

14.

Fermor B, Skerry T . PTH/PTHrP receptor expression on osteoblasts and osteocytes but not resorbing bone surfaces in growing rats. J Bone Miner Res. 1995; 10(12):1935-43. DOI: 10.1002/jbmr.5650101213. View

15.

Dasgupta R, Fuchs E . Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development. 1999; 126(20):4557-68. DOI: 10.1242/dev.126.20.4557. View

16.

Feng J, Ward L, Liu S, Lu Y, Xie Y, Yuan B . Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006; 38(11):1310-5. PMC: 1839871. DOI: 10.1038/ng1905. View

17.

NEUMAN W, NEUMAN M, Sammon P, CASARETT G . The metabolism of labeled parathyroid hormone. IV. Autoradiographic studies. Calcif Tissue Res. 1975; 18(4):263-70. DOI: 10.1007/BF02546245. View

18.

Miao D, He B, Jiang Y, Kobayashi T, Soroceanu M, Zhao J . Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest. 2005; 115(9):2402-11. PMC: 1193882. DOI: 10.1172/JCI24918. View

19.

Kalajzic I, Braut A, Guo D, Jiang X, Kronenberg M, Mina M . Dentin matrix protein 1 expression during osteoblastic differentiation, generation of an osteocyte GFP-transgene. Bone. 2004; 35(1):74-82. DOI: 10.1016/j.bone.2004.03.006. View

20.

Tomkinson A, Reeve J, Shaw R, Noble B . The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. J Clin Endocrinol Metab. 1997; 82(9):3128-35. DOI: 10.1210/jcem.82.9.4200. View