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• W2077994489 abstract "Mechanical strain and estrogens both stimulate osteoblast proliferation through estrogen receptor (ER)-mediated effects, and both down-regulate the Wnt antagonist Sost/sclerostin. Here, we investigate the differential effects of ERα and -β in these processes in mouse long bone-derived osteoblastic cells and human Saos-2 cells. Recruitment to the cell cycle following strain or 17β-estradiol occurs within 30 min, as determined by Ki-67 staining, and is prevented by the ERα antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride. ERβ inhibition with 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-β]pyrimidin-3-yl] phenol (PTHPP) increases basal proliferation similarly to strain or estradiol. Both strain and estradiol down-regulate Sost expression, as does in vitro inhibition or in vivo deletion of ERα. The ERβ agonists 2,3-bis(4-hydroxyphenyl)-propionitrile and ERB041 also down-regulated Sost expression in vitro, whereas the ERα agonist 4,4′,4″-[4-propyl-(1H)-pyrazol-1,3,5-triyl]tris-phenol or the ERβ antagonist PTHPP has no effect. Tamoxifen, a nongenomic ERβ agonist, down-regulates Sost expression in vitro and in bones in vivo. Inhibition of both ERs with fulvestrant or selective antagonism of ERβ, but not ERα, prevents Sost down-regulation by strain or estradiol. Sost down-regulation by strain or ERβ activation is prevented by MEK/ERK blockade. Exogenous sclerostin has no effect on estradiol-induced proliferation but prevents that following strain. Thus, in osteoblastic cells the acute proliferative effects of both estradiol and strain are ERα-mediated. Basal Sost down-regulation follows decreased activity of ERα and increased activity of ERβ. Sost down-regulation by strain or increased estrogens is mediated by ERβ, not ERα. ER-targeting therapy may facilitate structurally appropriate bone formation by enhancing the distinct ligand-independent, strain-related contributions to proliferation of both ERα and ERβ. Mechanical strain and estrogens both stimulate osteoblast proliferation through estrogen receptor (ER)-mediated effects, and both down-regulate the Wnt antagonist Sost/sclerostin. Here, we investigate the differential effects of ERα and -β in these processes in mouse long bone-derived osteoblastic cells and human Saos-2 cells. Recruitment to the cell cycle following strain or 17β-estradiol occurs within 30 min, as determined by Ki-67 staining, and is prevented by the ERα antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride. ERβ inhibition with 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-β]pyrimidin-3-yl] phenol (PTHPP) increases basal proliferation similarly to strain or estradiol. Both strain and estradiol down-regulate Sost expression, as does in vitro inhibition or in vivo deletion of ERα. The ERβ agonists 2,3-bis(4-hydroxyphenyl)-propionitrile and ERB041 also down-regulated Sost expression in vitro, whereas the ERα agonist 4,4′,4″-[4-propyl-(1H)-pyrazol-1,3,5-triyl]tris-phenol or the ERβ antagonist PTHPP has no effect. Tamoxifen, a nongenomic ERβ agonist, down-regulates Sost expression in vitro and in bones in vivo. Inhibition of both ERs with fulvestrant or selective antagonism of ERβ, but not ERα, prevents Sost down-regulation by strain or estradiol. Sost down-regulation by strain or ERβ activation is prevented by MEK/ERK blockade. Exogenous sclerostin has no effect on estradiol-induced proliferation but prevents that following strain. Thus, in osteoblastic cells the acute proliferative effects of both estradiol and strain are ERα-mediated. Basal Sost down-regulation follows decreased activity of ERα and increased activity of ERβ. Sost down-regulation by strain or increased estrogens is mediated by ERβ, not ERα. ER-targeting therapy may facilitate structurally appropriate bone formation by enhancing the distinct ligand-independent, strain-related contributions to proliferation of both ERα and ERβ. Bone architecture is adjusted to be functionally appropriate for load-bearing through processes in which the strains engendered by loading initiate cascades of responses in resident bone cells that in turn influence the activity of cells responsible for bone formation and resorption. The activity of these cells is also influenced by estrogens. Loss of estrogens following menopause is associated with the development of osteoporosis, a widespread condition of skeletal inadequacy that has been hypothesized to reflect a failure of the homeostatic mechanisms by which bone adapts to its functional load-bearing environment, commonly referred to as the mechanostat (1Lanyon L. Skerry T. Postmenopausal osteoporosis as a failure of bone's adaptation to functional loading: a hypothesis.J. Bone Miner. Res. 2001; 16: 1937-1947Crossref PubMed Google Scholar). The cellular mechanisms of the mechanostat are locally influenced by the estrogen receptors ERα 7The abbreviations used are: ERestrogen receptorMPP1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloridePTHPP4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-β]pyrimidin-3-yl]phenolPPT4,4′,4“-[4-propyl-(1H)-pyrazol-1,3,5-triyl]tris-phenolDPN2,3-bis(4-hydroxyphenyl)-propionitrileE217β-estradiolβ2-MGβ2-microglobulinLRPlow density lipoprotein receptor-related proteinCLBObscortical long bone osteoblastic cellsrhSOSTrecombinant human sclerostin. and ERβ acting ligand-independently (2Saxon L.K. Galea G. Meakin L. Price J. Lanyon L.E. Estrogen receptors α and β have different gender-dependent effects on the adaptive responses to load bearing in cancellous and cortical bone.Endocrinology. 2012; 153: 2254-2266Crossref PubMed Scopus (45) Google Scholar, 3Lanyon L. Armstrong V. Saxon L. Sunters A. Sugiyama T. Zaman G. Price J. Estrogen receptors critically regulate bones' adaptive responses to loading.Clin. Rev. Bone Miner. Metab. 2007; 5: 234-248Crossref Scopus (0) Google Scholar, 4Windahl S.H. Saxon L. Börjesson A.E. Lagerquist M.K. Frenkel B. Henning P. Lerner U.H. Galea G.L. Meakin L.B. Engdahl C. Sjögren K. Antal M.C. Krust A. Chambon P. Lanyon L.E. Price J.S. Ohlsson C. Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2.J. Bone Miner. Res. 2013; 28: 291-301Crossref PubMed Scopus (60) Google Scholar). This implies that compounds that target the ERs should be able to enhance the sensitivity of the mechanostat and so provide effective, mechanically appropriate, treatment for osteoporosis. The action of the selective estrogen receptor modulator tamoxifen illustrates this; it reduces fracture risk in human patients (5Cooke A.L. Metge C. Lix L. Prior H.J. Leslie W.D. Tamoxifen use and osteoporotic fracture risk: a population-based analysis.J. Clin. Oncol. 2008; 26: 5227-5232Crossref PubMed Scopus (56) Google Scholar), and in mice it synergistically enhances the effects of loading on bone gain (6Sugiyama T. Galea G.L. Lanyon L.E. Price J.S. Mechanical loading-related bone gain is enhanced by tamoxifen but unaffected by fulvestrant in female mice.Endocrinology. 2010; 151: 5582-5590Crossref PubMed Scopus (35) Google Scholar). estrogen receptor 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-β]pyrimidin-3-yl]phenol 4,4′,4“-[4-propyl-(1H)-pyrazol-1,3,5-triyl]tris-phenol 2,3-bis(4-hydroxyphenyl)-propionitrile 17β-estradiol β2-microglobulin low density lipoprotein receptor-related protein cortical long bone osteoblastic cells recombinant human sclerostin. Loading-induced increases in bone formation involve osteoblastic cell proliferation (7Pead M.J. Skerry T.M. Lanyon L.E. Direct transformation from quiescence to bone formation in the adult periosteum following a single brief period of bone loading.J. Bone Miner. Res. 1988; 3: 647-656Crossref PubMed Google Scholar, 8Sakai D. Kii I. Nakagawa K. Matsumoto H.N. Takahashi M. Yoshida S. Hosoya T. Takakuda K. Kudo A. Remodeling of actin cytoskeleton in mouse periosteal cells under mechanical loading induces periosteal cell proliferation during bone formation.PLoS One. 2011; 6: e24847Crossref PubMed Scopus (0) Google Scholar) and down-regulation of Sost/sclerostin (9Robling A.G. Niziolek P.J. Baldridge L.A. Condon K.W. Allen M.R. Alam I. Mantila S.M. Gluhak-Heinrich J. Bellido T.M. Harris S.E. Turner C.H. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin.J. Biol. Chem. 2008; 283: 5866-5875Abstract Full Text Full Text PDF PubMed Scopus (861) Google Scholar, 10Moustafa A. Sugiyama T. Prasad J. Zaman G. Gross T.S. Lanyon L.E. Price J.S. Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered.Osteoporos. Int. 2012; 23: 1225-1234Crossref PubMed Scopus (157) Google Scholar, 11Tu X. Rhee Y. Condon K.W. Bivi N. Allen M.R. Dwyer D. Stolina M. Turner C.H. Robling A.G. Plotkin L.I. Bellido T. Sost down-regulation and local Wnt signaling are required for the osteogenic response to mechanical loading.Bone. 2012; 50: 209-217Crossref PubMed Scopus (289) Google Scholar), a glycoprotein secreted primarily by osteocytes. Although a direct effect of sclerostin on strain-induced osteoblast proliferation has never been shown, sclerostin is presumed to exert its potent anti-osteogenic effect through inhibition of the Wnt pathway in neighboring osteoblasts by antagonizing Wnts binding to their low density lipoprotein receptor-related (LRP)-5 and -6 co-receptors (12Krause C. Korchynskyi O. de Rooij K. Weidauer S.E. de Gorter D.J. van Bezooijen R.L. Hatsell S. Economides A.N. Mueller T.D. Löwik C.W. ten Dijke P. Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways.J. Biol. Chem. 2010; 285: 41614-41626Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Neutralizing antibodies against sclerostin appear to have substantial and sustained osteogenic effects in humans and are now in advanced stages of clinical trials for the treatment of osteoporosis (13Padhi D. Jang G. Stouch B. Fang L. Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody.J. Bone Miner. Res. 2011; 26: 19-26Crossref PubMed Scopus (582) Google Scholar). A reduction in sclerostin production is also achieved by treatment with estrogens (14Mödder U.I. Clowes J.A. Hoey K. Peterson J.M. McCready L. Oursler M.J. Riggs B.L. Khosla S. Regulation of circulating sclerostin levels by sex steroids in women and in men.J. Bone Miner. Res. 2011; 26: 27-34Crossref PubMed Scopus (0) Google Scholar, 15Zhang J. Lazarenko O.P. Wu X. Tong Y. Blackburn M.L. Gomez-Acevedo H. Shankar K. Badger T.M. Ronis M.J. Chen J.R. Differential effects of short term feeding of a soy protein isolate diet and estrogen treatment on bone in the pre-pubertal rat.PLoS One. 2012; 7: e35736Crossref PubMed Scopus (0) Google Scholar), which also increase osteoblast proliferation (16Ogita M. Rached M.T. Dworakowski E. Bilezikian J.P. Kousteni S. Differentiation and proliferation of periosteal osteoblast progenitors are differentially regulated by estrogens and intermittent parathyroid hormone administration.Endocrinology. 2008; 149: 5713-5723Crossref PubMed Scopus (0) Google Scholar). However, the mechanisms by which estrogens and loading converge to achieve similar outcomes remain largely unknown. To investigate the potential mechanisms involved, we have established a model in which human female osteoblastic Saos-2 cells are subjected to mechanical strain by four-point bending of their substrate in vitro (17Galea G.L. Sunters A. Meakin L.B. Zaman G. Sugiyama T. Lanyon L.E. Price J.S. Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4.FEBS Lett. 2011; 585: 2450-2454Crossref PubMed Scopus (67) Google Scholar). These cells have been reported by ourselves and others to express Sost and sclerostin protein (17Galea G.L. Sunters A. Meakin L.B. Zaman G. Sugiyama T. Lanyon L.E. Price J.S. Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4.FEBS Lett. 2011; 585: 2450-2454Crossref PubMed Scopus (67) Google Scholar, 18Yu L. van der Valk M. Cao J. Han C.Y. Juan T. Bass M.B. Deshpande C. Damore M.A. Stanton R. Babij P. Sclerostin expression is induced by BMPs in human Saos-2 osteosarcoma cells but not via direct effects on the sclerostin gene promoter or ECR5 element.Bone. 2011; 49: 1131-1140Crossref PubMed Scopus (23) Google Scholar). In this model, exposure to strain causes down-regulation of Sost expression over a time course consistent with that observed following loading of rodent bones in vivo (19Zaman G. Saxon L.K. Sunters A. Hilton H. Underhill P. Williams D. Price J.S. Lanyon L.E. Loading-related regulation of gene expression in bone in the contexts of estrogen deficiency, lack of estrogen receptor α, and disuse.Bone. 2010; 46: 628-642Crossref PubMed Scopus (0) Google Scholar, 20Mantila Roosa S.M. Liu Y. Turner C.H. Gene expression patterns in bone following mechanical loading.J. Bone Miner. Res. 2011; 26: 100-112Crossref PubMed Scopus (105) Google Scholar), through mechanisms requiring extracellular signal-regulated kinase (ERK) signaling (17Galea G.L. Sunters A. Meakin L.B. Zaman G. Sugiyama T. Lanyon L.E. Price J.S. Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4.FEBS Lett. 2011; 585: 2450-2454Crossref PubMed Scopus (67) Google Scholar). ERK is activated in bones subjected to loading in vivo (21Li Y. Ge C. Long J.P. Begun D.L. Rodriguez J.A. Goldstein S.A. Franceschi R.T. Biomechanical stimulation of osteoblast gene expression requires phosphorylation of the RUNX2 transcription factor.J. Bone Miner. Res. 2012; 27: 1263-1274Crossref PubMed Scopus (58) Google Scholar) and in osteoblastic cells subjected to strain in vitro (22Jessop H.L. Rawlinson S.C. Pitsillides A.A. Lanyon L.E. Mechanical strain and fluid movement both activate extracellular regulated kinase (ERK) in osteoblast-like cells but via different signaling pathways.Bone. 2002; 31: 186-194Crossref PubMed Scopus (131) Google Scholar, 23Jessop H.L. Sjöberg M. Cheng M.Z. Zaman G. Wheeler-Jones C.P. Lanyon L.E. Mechanical strain and estrogen activate estrogen receptor α in bone cells.J. Bone Miner. Res. 2001; 16: 1045-1055Crossref PubMed Scopus (100) Google Scholar, 24Aguirre J.I. Plotkin L.I. Gortazar A.R. Millan M.M. O'Brien C.A. Manolagas S.C. Bellido T. A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction.J. Biol. Chem. 2007; 282: 25501-25508Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). This involves ERα and ERβ acting ligand-independently (24Aguirre J.I. Plotkin L.I. Gortazar A.R. Millan M.M. O'Brien C.A. Manolagas S.C. Bellido T. A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction.J. Biol. Chem. 2007; 282: 25501-25508Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Other effects of strain on ligand-independent ER activity include activation of genomic estrogen-response elements (25Zaman G. Cheng M.Z. Jessop H.L. White R. Lanyon L.E. Mechanical strain activates estrogen response elements in bone cells.Bone. 2000; 27: 233-239Crossref PubMed Scopus (82) Google Scholar), ERα-mediated nongenomic activation of Wnt/β-catenin (26Armstrong V.J. Muzylak M. Sunters A. Zaman G. Saxon L.K. Price J.S. Lanyon L.E. Wnt/β-catenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor α.J. Biol. Chem. 2007; 282: 20715-20727Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 27Sunters A. Armstrong V.J. Zaman G. Kypta R.M. Kawano Y. Lanyon L.E. Price J.S. Mechano-transduction in osteoblastic cells involves strain-regulated estrogen receptor α-mediated control of insulin-like growth factor (IGF) I receptor sensitivity to ambient IGF, leading to phosphatidylinositol 3-kinase/AKT-dependent Wnt/LRP5 receptor-independent activation of β-catenin signaling.J. Biol. Chem. 2010; 285: 8743-8758Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), and AKT (27Sunters A. Armstrong V.J. Zaman G. Kypta R.M. Kawano Y. Lanyon L.E. Price J.S. Mechano-transduction in osteoblastic cells involves strain-regulated estrogen receptor α-mediated control of insulin-like growth factor (IGF) I receptor sensitivity to ambient IGF, leading to phosphatidylinositol 3-kinase/AKT-dependent Wnt/LRP5 receptor-independent activation of β-catenin signaling.J. Biol. Chem. 2010; 285: 8743-8758Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar) signaling. Osteoblastic cells from wild type (WT) mice proliferate in response to strain in the absence of estrogenic ligands, whereas similarly derived cells from ERα−/− mice do not (28Jessop H.L. Suswillo R.F. Rawlinson S.C. Zaman G. Lee K. Das-Gupta V. Pitsillides A.A. Lanyon L.E. Osteoblast-like cells from estrogen receptor α knockout mice have deficient responses to mechanical strain.J. Bone Miner. Res. 2004; 19: 938-946Crossref PubMed Scopus (74) Google Scholar, 29Damien E. Price J.S. Lanyon L.E. Mechanical strain stimulates osteoblast proliferation through the estrogen receptor in males as well as females.J. Bone Miner. Res. 2000; 15: 2169-2177Crossref PubMed Google Scholar). Consistent with this observation, cells overexpressing ERα are more proliferative in response to strain than cells only expressing endogenous ERα (25Zaman G. Cheng M.Z. Jessop H.L. White R. Lanyon L.E. Mechanical strain activates estrogen response elements in bone cells.Bone. 2000; 27: 233-239Crossref PubMed Scopus (82) Google Scholar). The role of ERα in bones' local adaptive responses to loading has also been demonstrated in vivo in a number of studies, each of which show a diminished response to loading in female mice when ERα activity is reduced (2Saxon L.K. Galea G. Meakin L. Price J. Lanyon L.E. Estrogen receptors α and β have different gender-dependent effects on the adaptive responses to load bearing in cancellous and cortical bone.Endocrinology. 2012; 153: 2254-2266Crossref PubMed Scopus (45) Google Scholar, 30Lee K. Jessop H. Suswillo R. Zaman G. Lanyon L. Endocrinology: bone adaptation requires oestrogen receptor-α.Nature. 2003; 424: 389Crossref PubMed Google Scholar, 31Callewaert F. Bakker A. Schrooten J. Van Meerbeek B. Verhoeven G. Boonen S. Vanderschueren D. Androgen receptor disruption increases the osteogenic response to mechanical loading in male mice.J. Bone Miner. Res. 2010; 25: 124-131Crossref PubMed Scopus (51) Google Scholar, 32Lee K.C. Jessop H. Suswillo R. Zaman G. Lanyon L.E. The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-α and -β.J. Endocrinol. 2004; 182: 193-201Crossref PubMed Scopus (94) Google Scholar). In contrast, the role of ERβ in regulating bones' adaptation to loading remains controversial. The first in vivo study of ER's involvement in loading-related adaptation in bone reported a lower osteogenic response to axial loading of the ulna in female ERβ−/− mice compared with WT littermates (32Lee K.C. Jessop H. Suswillo R. Zaman G. Lanyon L.E. The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-α and -β.J. Endocrinol. 2004; 182: 193-201Crossref PubMed Scopus (94) Google Scholar). However, later studies using knock-outs regarded as being more “complete,” showed enhanced responses to axial loading (2Saxon L.K. Galea G. Meakin L. Price J. Lanyon L.E. Estrogen receptors α and β have different gender-dependent effects on the adaptive responses to load bearing in cancellous and cortical bone.Endocrinology. 2012; 153: 2254-2266Crossref PubMed Scopus (45) Google Scholar, 33Saxon L.K. Robling A.G. Castillo A.B. Mohan S. Turner C.H. The skeletal responsiveness to mechanical loading is enhanced in mice with a null mutation in estrogen receptor-β.Am. J. Physiol. Endocrinol. Metab. 2007; 293: E484-E491Crossref PubMed Scopus (0) Google Scholar). ERβ has been suggested to be the dominant regulator of estrogen receptor signaling, in part due to its ability to form heterodimers with ERα (34Pettersson K. Delaunay F. Gustafsson J.A. Estrogen receptor β acts as a dominant regulator of estrogen signaling.Oncogene. 2000; 19: 4970-4978Crossref PubMed Google Scholar). However, the outcomes of ERβ signaling depend on the cellular context in which it operates; whereas ERβ largely inhibits transcriptomic changes caused by estrogen treatment when ERα is present, it promotes expression of a subset of genes when ERα is deleted (35Lindberg M.K. Movérare S. Skrtic S. Gao H. Dahlman-Wright K. Gustafsson J.A. Ohlsson C. Estrogen receptor (ER) β reduces ERα-regulated gene transcription, supporting a “ying yang” relationship between ERα and ERβ in mice.Mol. Endocrinol. 2003; 17: 203-208Crossref PubMed Scopus (0) Google Scholar). In osteoblastic cells, ERα activation increases ERβ expression (36Somjen D. Katzburg S. Sharon O. Knoll E. Hendel D. Stern N. Sex-specific response of cultured human bone cells to ERα and ERβ-specific agonists by modulation of cell proliferation and creatine kinase-specific activity.J. Steroid Biochem. Mol. Biol. 2011; 125: 226-230Crossref PubMed Scopus (8) Google Scholar) and has been shown to directly bind the ERβ promoter in other cell types (37Kietz S. Thomsen J.S. Matthews J. Pettersson K. Ström A. Gustafsson J.A. The Ah receptor inhibits estrogen-induced estrogen receptor β in breast cancer cells.Biochem. Biophys. Res. Commun. 2004; 320: 76-82Crossref PubMed Scopus (23) Google Scholar). In contrast, ERβ can repress ERα expression (38Bartella V. Rizza P. Barone I. Zito D. Giordano F. Giordano C. Catalano S. Mauro L. Sisci D. Panno M.L. Fuqua S.A. Andò S. Estrogen receptor β binds Sp1 and recruits a corepressor complex to the estrogen receptor α gene promoter.Breast Cancer Res. Treat. 2012; 134: 569-581Crossref PubMed Scopus (0) Google Scholar), and mice lacking ERβ have increased ERα in their bones (39Windahl S.H. Hollberg K. Vidal O. Gustafsson J.A. Ohlsson C. Andersson G. Female estrogen receptor β−/− mice are partially protected against age-related trabecular bone loss.J. Bone Miner. Res. 2001; 16: 1388-1398Crossref PubMed Google Scholar). The outcomes of ERα and ERβ signaling are therefore closely linked in what has been described as a “ying yang” relationship determined by a subtle balance between them (35Lindberg M.K. Movérare S. Skrtic S. Gao H. Dahlman-Wright K. Gustafsson J.A. Ohlsson C. Estrogen receptor (ER) β reduces ERα-regulated gene transcription, supporting a “ying yang” relationship between ERα and ERβ in mice.Mol. 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Double oestrogen receptor α and β knockout mice reveal differences in neural oestrogen-mediated progestin receptor induction and female sexual behaviour.J. Neuroendocrinol. 2003; 15: 978-983Crossref PubMed Scopus (0) Google Scholar). Having originally reported the involvement of the ERs in bones' adaptive response to loading (30Lee K. Jessop H. Suswillo R. Zaman G. Lanyon L. Endocrinology: bone adaptation requires oestrogen receptor-α.Nature. 2003; 424: 389Crossref PubMed Google Scholar, 32Lee K.C. Jessop H. Suswillo R. Zaman G. Lanyon L.E. The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-α and -β.J. Endocrinol. 2004; 182: 193-201Crossref PubMed Scopus (94) Google Scholar), and more recently ERK's involvement in Sost down-regulation by mechanical strain in vitro (17Galea G.L. Sunters A. Meakin L.B. Zaman G. Sugiyama T. Lanyon L.E. Price J.S. Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4.FEBS Lett. 2011; 585: 2450-2454Crossref PubMed Scopus (67) Google Scholar), we hypothesized that these commonalities between estrogen and strain signaling meant that ERα and ERβ could both contribute to the ligand-independent mechanisms by which loading down-regulates Sost expression and in turn regulates proliferation of osteoblasts in response to strain. The studies reported here used subtype-selective receptor agonists and antagonists against the ERs to establish the contributions of ERα and ERβ to the regulation of Sost and proliferation by both estradiol and strain in osteoblasts. 17β-Estradiol (E2) was from Sigma and dissolved in molecular grade ethanol (EOH). Selective estrogen receptor modulators used were the ERα-selective agonist 4,4′,4“-[4-propyl-(1H)-pyrazol-1,3,5-triyl]tris-phenol (PPT, 0.1 μm) (44Stauffer S.R. Coletta C.J. Tedesco R. Nishiguchi G. Carlson K. Sun J. Katzenellenbogen B.S. Katzenellenbogen J.A. Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-α-selective agonists.J. Med. Chem. 2000; 43: 4934-4947Crossref PubMed Scopus (661) Google Scholar) or antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP, 0.1 μm) (45Harrington W.R. Sheng S. Barnett D.H. Petz L.N. Katzenellenbogen J.A. Katzenellenbogen B.S. Activities of estrogen receptor α- and β-selective ligands at diverse estrogen-responsive gene sites mediating transactivation or transrepression.Mol. Cell. Endocrinol. 2003; 206: 13-22Crossref PubMed Scopus (0) Google Scholar), the ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN, 0.1 μm) (46Meyers M.J. Sun J. Carlson K.E. Marriner G.A. Katzenellenbogen B.S. Katzenellenbogen J.A. Estrogen receptor-β potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues.J. Med. Chem. 2001; 44: 4230-4251Crossref PubMed Scopus (577) Google Scholar) or antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-β]pyrimidin-3-yl] phenol (PTHPP, 0.1 μm) (47Compton D.R. Sheng S. Carlson K.E. Rebacz N.A. Lee I.Y. Katzenellenbogen B.S. Katzenellenbogen J.A. Pyrazolo[1,5-a]pyrimidines: estrogen receptor ligands possessing estrogen receptor β antagonist activity.J. Med. Chem. 2004; 47: 5872-5893Crossref PubMed Scopus (0) Google Scholar), the context-dependent agonist/antagonist tamoxifen (0.1 μm), and the nonselective ERα/ERβ antagonist fulvestrant (0.1 μm, ICI 182780). The mitogen-activated protein kinase (MAPK)/ERK inhibitor PD98059 was used at a final concentration of 10 μm. All were from Tocris Bioscience (Bristol, UK). Fulvestrant was dissolved in EOH, and all other compounds were dissolved in dimethyl sulfoxide (DMSO). Cells were pretreated with the selective antagonists MPP, PTHPP, and PD98059 30 min before strain or E2 treatment, whereas fulvestrant was added 16 h before as described previously (27Sunters A. Armstrong V.J. Zaman G. Kypta R.M. Kawano Y. Lanyon L.E. Price J.S. Mechano-transduction in osteoblastic cells involves strain-regulated estrogen receptor α-mediated control of insulin-like growth factor (IGF) I receptor sensitivity to ambient IGF, leading to phosphatidylinositol 3-kinase/AKT-dependent Wnt/LRP5 receptor-independent activation of β-catenin signaling.J. Biol. Chem. 2010; 285: 8743-8758Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Wnt3a and recombinant human sclerostin were from R&D Systems (Abingdon, UK). Sclerostin was dissolved in phosphate-buffered saline (PBS) and added 1 h before strain or E2 treatment. The diluents never reached concentrations greater than 0.1% in the culture medium. All cells were maintained in phenol red-free DMEM containing 10% heat-inactivated FCS (PAA, Somerset, UK), 2 mm l-glutamine, 100 IU/ml penicillin, and 100 IU/ml streptomycin (Invitrogen) (complete medium) in a 37 °C incubator at 5% CO2, 95% humidity as described previously (17Galea G.L. Sunters A. Meakin L.B. Zaman G. Sugiyama T. Lanyon L.E. Price J.S. Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4.FEBS Lett. 2011; 585: 2450-2454Crossref PubMed Scopus (67) Google Scholar). Saos-2 cells were a kind gift of Dr. S. Allen (Royal Veterinary College, London, UK). Mouse cortical long bone osteoblastic cells (cLBObs) were derived from explants of young adult female C57BL/6 mice as described previously (26Armstrong V.J. Muzylak M. Sunters A. Zaman G. Saxon L.K. Price J.S. Lanyon L.E. Wnt/β-catenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor α.J. Biol. Chem. 2007; 282: 20715-20727Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 28Jessop H.L. Suswillo R.F. Rawlinson S.C. Zaman G. Lee K. Das-Gupta V. Pitsillides A.A. Lanyon L.E. Osteoblast-like cells" @default.
• W2077994489 created "2016-06-24" @default.
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• W2077994489 date "2013-03-01" @default.
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• W2077994489 title "Estrogen Receptor α Mediates Proliferation of Osteoblastic Cells Stimulated by Estrogen and Mechanical Strain, but Their Acute Down-regulation of the Wnt Antagonist Sost Is Mediated by Estrogen Receptor β" @default.
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