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Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption–formation cycles?

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Abstract

Osteocytes, entrapped within a newly mineralized bone matrix, possess a unique cellular identity due to a specialized morphology and a molecular signature. These features endow them to serve as a bone response mechanism for mechanical stress in their microenvironment. Sclerostin, a primarily osteocyte product, is widely considered as a mechanotranduction key molecule whose expression is suppressed by mechanical loading, or it is induced by unloading. This review presents a model suggesting that sclerostin is major mediator for integrating mechanical, local, and hormonal signals, sensed by the osteocytes, in controlling the remodeling apparatus. This central role is achieved through interplay between two opposing mechanisms: (1) unloading-induced high sclerostin levels, which antagonize Wnt-canonical-β-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechanical loading results in low sclerostin levels, activation of Wnt-canonical signaling, and bone formation. Therefore, adaptive bone remodeling occurring at a distinct bone compartment is orchestrated by altered sclerostin levels, which regulate the expression of the other osteocyte-specific proteins, such as RANKL, OPG, and proteins encoded by “mineralization-related genes” (DMP1, PHEX, and probably FGF23). For example, under specific terms, sclerostin regulates differential RANKL and OPG production, and creates a dynamic RANKL/OPG ratio, leading either to bone formation or resorption. It also controls the expression of PHEX, DMP1, and most likely FGF23, leading to either bone matrix mineralization or its inhibition. Such opposing up- or down-regulation of remodeling phases allows osteocytes to function as an “external unit”, ensuring transition from bone resorption to bone formation.

Mini Abstract: The osteocyte network plays a central role in directing bone response either to mechanical loading, or to unloading, leading correspondingly to bone formation or resorption. This review shows a key role of the osteocyte-produced sclerostin as a major mediator of the molecular mechanisms involved in the process of adaptive bone remodeling

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References

  1. Sims NA, Martin TJ (2014) Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BoneKey Rep 3:481. doi:10.1038/bonekey.2013.215

    PubMed  Google Scholar 

  2. Cranney A, Jamal SA, Tsang JF, Josse RG, Leslie WD (2007) Low bone mineral density and fracture burden in postmenopausal women. CMAJ 177:575–580

    PubMed Central  PubMed  Google Scholar 

  3. Raggatt LJ, Partridge NC (2010) Cellular and molecular mechanisms of bone remodeling. J Biol Chem 285:25103–25108

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Feng X, McDonald JM (2011) Disorders of bone remodeling. Ann Rev Pathol Mech Dis 6:121–145

    CAS  Google Scholar 

  5. Kular J, Tickner J, Chim SM, Xu J (2012) An overview of the regulation of bone remodelling at the cellular level. Clin Biochem 45:863–873

    CAS  PubMed  Google Scholar 

  6. Chim SM, Tickner J, Chow ST, Kuek V, Guo B, Zhang G, Rosen V, Erber W, Xu J (2013) Angiogenic factors in bone local environment. Cytokine Growth Factor Rev 24:297–310

    CAS  PubMed  Google Scholar 

  7. Parfitt AM (2008) Skeletal heterogeneity and the purposes of bone remodeling: implications for the understanding of osteoporosis. In: Marcus R, Feldman D, Nelson DA, Rosen CJ (eds) Osteoporosis. Elsevier, San Diego, pp 71–92

    Google Scholar 

  8. Franz-Odendaal TA, Hall BK, Witten PE (2006) Buried alive: how osteoblasts become osteocytes. Dev Dyn 235:176–190

    CAS  PubMed  Google Scholar 

  9. Bonewald LF (2007) Osteocytes as dynamic multifunctional cells. Ann N Y Acad Sci 1116:281–290

    CAS  PubMed  Google Scholar 

  10. Knothe Tate ML, Niederer P, Knothe U (1998) In vivo tracer transport through the lacunocanalicular system of rat bone in an environment devoid of mechanical loading. Bone 22:107–117

    CAS  PubMed  Google Scholar 

  11. Kamioka H, Sugawara Y, Honjo T, Yamashiro T, Takano-Yamamoto T (2004) Terminal differentiation of osteoblasts to osteocytes is accompanied by dramatic changes in the distribution of actin-binding proteins. J Bone Miner Res 19:471–478

    CAS  PubMed  Google Scholar 

  12. Bellido T (2014) Osteocyte-driven bone remodeling. Calcif Tissue Int 94:25–34

    CAS  PubMed  Google Scholar 

  13. Skerry TM (2008) The response of bone to mechanical loading and disuse: fundamental principles and influences on osteoblast/osteocyte homeostasis. Arch Biochem Biophys 473:117–123

    CAS  PubMed  Google Scholar 

  14. Rubin CT, Lanyon LE (1987) Kappa delta award paper. Osteoregulatory nature of mechanical stimuli: function as a determinant for adaptive remodeling in bone. J Orthop Res 5:300–310

    CAS  PubMed  Google Scholar 

  15. Cowin SC, Sadegh AM, Luo GM (1992) An evolutionary Wolff’s law for trabecular architecture. J Biomech Eng 114:129–136

    CAS  PubMed  Google Scholar 

  16. Wang X, Dumas GA (2002) Simulation of bone adaptive remodeling using a stochastic process as loading history. J Biomech 35:375–380

    PubMed  Google Scholar 

  17. Skerry TM (2006) One mechanostat or many? Modifications of the site-specific response of bone to mechanical loading by nature and nurture. J Musculoskelet Neuronal Interact 6:122–127

    CAS  PubMed  Google Scholar 

  18. McNamaraa LM, Van der Lindenb JC, Weinansb H, Prendergast PJ (2006) Stress-concentrating effect of resorption lacunae in trabecular bone. J Biomech 39:734–741

    Google Scholar 

  19. Smit TH, Burger EH (2000) Is BMU-coupling a strain-regulated phenomenon? A finite element analysis. J Bone Miner Res 15:301–307

    CAS  PubMed  Google Scholar 

  20. Prendergast PJ, Huiskes R (1996) Microdamage and osteocyte-lacuna strain in bone: a microstructural finite element analysis. J Biomech Eng 118:240–246

    CAS  PubMed  Google Scholar 

  21. Mori S, Burr DB (1993) Increased intracortical remodeling following fatigue damage. Bone 14:103–109

    CAS  PubMed  Google Scholar 

  22. Van der Linden JC, Homminga J, Verhaar JA, Weinans H (2001) Mechanical consequences of bone loss in cancellous bone. J Bone Miner Res 16:457–465

    PubMed  Google Scholar 

  23. Dallas SL, Prideaux M, Bonewald LF (2013) The osteocyte: an endocrine cell … and more. Endocr Rev. doi:10.1210/er.2012-1026

    PubMed Central  PubMed  Google Scholar 

  24. Rochefort GY, Pallu S, Benhamou CL (2010) Osteocyte: the unrecognized side of bone tissue. Osteoporos Int 21:1457–1469

    CAS  PubMed  Google Scholar 

  25. Klein-Nulend J, Bakker AD, Bacabac RG, Vatsa A, Weinbaum S (2013) Mechanosensation and transduction in osteocytes. Bone 54:182–190

    CAS  PubMed  Google Scholar 

  26. Delgado-Calle J, Sanudo C, Bolado A, Fernandez A, Arozamena J, Pascual-Carra MA, Rodriguez-Rey JC, Fraga M, Bonewald LF, Riancho JA (2012) DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J Bone Miner Res 27:926–937

    CAS  PubMed  Google Scholar 

  27. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543

    CAS  PubMed  Google Scholar 

  28. Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869

    PubMed  Google Scholar 

  30. Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L (2009) Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/betacatenin signaling. J Bone Miner Res 24:1651–1661

    CAS  PubMed  Google Scholar 

  31. Collette NM, Genetos DC, Economides AN, Xie L, Shahnazari M, Yao W, Lane NE, Harland RM, Loots GG (2012) Targeted deletion of Sost distal enhancer increases bone formation and bone mass. Proc Natl Acad Sci U S A 109:14092–14097

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Tu X, Rhee Y, Condon KW, Bivi N, Allen MR, Dwyer D, Stolina M, Turner CH, Robling AG, Plotkin LI, Bellido T (2012) Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone 50:209–217

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Lewiecki EM (2009) Emerging drugs for postmenopausal osteoporosis. Expert Opin Emerg Drugs 14:129–144

    CAS  PubMed  Google Scholar 

  35. Padhi D, Jang G, Stouch B, Fang L, Posvar E (2011) Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res 26:19–26

    CAS  PubMed  Google Scholar 

  36. McColm J, Hu L, Womack T, Tang CC, Chiang AY (2014) Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J Bone Miner Res 29:935–943

    CAS  PubMed  Google Scholar 

  37. Spatz JM, Ellman R, Cloutier AM, Louis L, van Vliet M, Suva LJ, Dwyer D, Stolina M, Ke HZ, Bouxsein ML (2013) Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. J Bone Miner Res 28:865–874

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Papapoulos SE (2011) Targeting sclerostin as potential treatment of osteoporosis. Ann Rheum Dis 70(Suppl 1):i119–i122

    CAS  PubMed  Google Scholar 

  39. Li X, Grisanti M, Fan W, Asuncion FJ, Tan HL, Dwyer D, Han CY, Yu L, Lee J, Lee E, Barrero M, Kurimoto P, Niu QT, Geng Z, Winters A, Horan T, Steavenson S, Jacobsen F, Chen Q, Haldankar R, Lavallee J, Tipton B, Daris M, Sheng J, Lu HS, Daris K, Deshpande R, Valente EG, Salimi-Moosavi H, Kostenuik PJ, Li J, Liu M, Li C, Lacey DL, Simonet WS, Ke HZ, Babij P, Stolina M, Ominsky MS, Richards WG (2011) Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J Bone Miner Res 26:2610–2621

    CAS  PubMed  Google Scholar 

  40. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE (2006) Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 38:1310–1315

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Sapir-Koren R, Livshits G (2011) Bone mineralization and regulation of phosphate homeostasis. IBMS BoneKEy 8:286–300

    Google Scholar 

  42. Bonewald LF (2011) The amazing osteocyte. J Bone Miner Res 26:229–238

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Guo R, Rowe PS, Liu S, Simpson LG, Xiao ZS, Quarles LD (2002) Inhibition of MEPE cleavage by Phex. Biochem Biophys Res Commun 297:38–45

    CAS  PubMed  Google Scholar 

  44. Liu S, Rowe PS, Vierthaler L, Zhou J, Quarles LD (2007) Phosphorylated acidic serine-aspartate-rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity. J Endocrinol 192:261–267

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD (2006) Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 291:E38–E49

    CAS  PubMed  Google Scholar 

  46. Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK (2013) Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 54:213–221

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Hamdy NA (2007) Targeting the RANK/RANKL/OPG signaling pathway: a novel approach in the management of osteoporosis. Curr Opin Investig Drugs 8:299–303

    CAS  PubMed  Google Scholar 

  48. Xu J, Wu HF, Ang ES, Yip K, Woloszyn M, Zheng MH, Tan RX (2009) Nf-kappab modulators in osteolytic bone diseases. Cytokine Growth Factor Rev 20:7–17

    CAS  PubMed  Google Scholar 

  49. Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, Gomibuchi T, Yano K, Shima N, Washida N, Tsuda E, Morinaga T, Higashio K, Ozawa H (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247:610–615

    CAS  PubMed  Google Scholar 

  50. Kramer I, Halleux C, Keller H, Pegurri M, Gooi JH, Weber PB, Feng JQ, Bonewald LF, Kneissel M (2010) Osteocyte Wnt/β-catenin signaling is required for normal bone homeostasis. Mol Cell Biol 30:3071–3085

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17:1231–1234

    CAS  PubMed  Google Scholar 

  52. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17:1235–1241

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Zhao S, Kato Y, Zhang YK, Harris S, Ahuja SS, Bonewald LF (2002) MLO-Y4 osteocyte-like cells support osteoclast formation and activation. J Bone Miner Res 17:2068–2079

    CAS  PubMed  Google Scholar 

  54. Kamioka H, Honjo T, Takano-Yamamoto T (2001) A three-dimensional distribution of osteocyte processes revealed by the combination of confocal laser scanning microscopy and differential interference contrast microscopy. Bone 28:145–149

    CAS  PubMed  Google Scholar 

  55. Honma M, Ikebuchi Y, Kariya Y, Hayashi M, Hayashi N, Aoki S, Suzuki H (2013) RANKL subcellular trafficking and regulatory mechanisms in osteocytes. J Bone Miner Res 28:1936–1949

    CAS  PubMed  Google Scholar 

  56. Corral DA, Amling M, Priemel M, Loyer E, Fuchs S, Ducy P, Baron R, Karsenty G (1998) Dissociation between bone resorption and bone formation in osteopenic transgenic mice. Proc Natl Acad Sci U S A 95:13835–13840

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Galli C, Fu Q, Wang W, Olsen BR, Manolagas SC, Jilka RL, O’Brien CA (2009) Commitment to the osteoblast lineage is not required for RANKL gene expression. J Biol Chem 284:12654–12662

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Xiong J, O’Brien CA (2012) Osteocyte RANKL: new insights into the control of bone remodeling. J Bone Miner Res 27:499–505

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Pierroz DD, Bonnet N, Baldock PA, Ominsky MS, Stolina M, Kostenuik PJ, Ferrari SL (2010) Are osteoclasts needed for the bone anabolic response to parathyroid hormone? A study of intermittent parathyroid hormone with denosumab or alendronate in knock-in mice expressing humanized RANKL. J Biol Chem 285:28164–28173

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA, Burnett-Bowie S-AM, Neer RM, Leder BZ (2013) Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 382:50–56

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810

    CAS  PubMed  Google Scholar 

  62. Gordon MD, Nusse R (2006) Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 281:22429–22433

    CAS  PubMed  Google Scholar 

  63. Maeda K, Takahashi N, Kobayashi Y (2013) Roles of Wnt signals in bone resorption during physiological and pathological states. J Mol Med 91:15–23

    CAS  PubMed  Google Scholar 

  64. Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA 2nd, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in LRP5, a Wnt coreceptor. J Cell Biol 157:303–314

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, Zhong Z, Matthes S, Jacobsen CM, Conlon RA, Brommage R, Liu Q, Mseeh F, Powell DR, Yang QM, Zambrowicz B, Gerrits H, Gossen JA, He X, Bader M, Williams BO, Warman ML, Robling AG (2011) LRP5 functions in bone to regulate bone mass. Nat Med 17:684–691

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Zhao L, Shim JW, Dodge TR, Robling AG, Yokota H (2013) Inactivation of Lrp5 in osteocytes reduces young’s modulus and responsiveness to the mechanical loading. Bone 54:35–43

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Glass DA II, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764

    CAS  PubMed  Google Scholar 

  68. Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, Deng L, Clemens TL, Williams BO (2005) Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem 280:21162–21168

    CAS  PubMed  Google Scholar 

  69. Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci U S A 105:20764–20769

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Wei W, Zeve D, Suh JM, Wang X, Du Y, Zerwekh JE, Dechow PC, Graff JM, Wan Y (2011) Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin. Mol Cell Biol 31:4706–4719

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42:606–615

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, Kikuchi Y, Takada I, Kato S, Kani S, Nishita M, Marumo K, Martin TJ, Minami Y, Takahashi N (2012) Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med 18:405–412

    CAS  PubMed  Google Scholar 

  73. Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192

    CAS  PubMed  Google Scholar 

  74. van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Löwik CW (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814

    PubMed Central  PubMed  Google Scholar 

  75. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. Faseb J 19:1842–1844

    CAS  PubMed  Google Scholar 

  76. Balemans W, Piters E, Cleiren E, Ai M, Van Wesenbeeck L, Warman ML, Van Hul W (2008) The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif Tissue Int 82:445–453

    CAS  PubMed  Google Scholar 

  77. Heino TJ, Kurata K, Higaki H, Vaananen HK (2009) Evidence for the role of osteocytes in the initiation of targeted remodeling. Technol Health Care 17:49–56

    PubMed  Google Scholar 

  78. van Oers RF, van Rietbergen B, Ito K, Hilbers PA, Huiskes R (2011) A sclerostin-based theory for strain-induced bone formation. Biomech Model Mechanobiol 10:663–670

    PubMed  Google Scholar 

  79. Tian X, Jee WS, Li X, Paszty C, Ke HZ (2011) Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. Bone 48:197–201

    CAS  PubMed  Google Scholar 

  80. Moustafa A, Sugiyama T, Prasad J, Zaman G, Gross TS, Lanyon LE, Price JS (2012) 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 23:1225–1234

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Ryan ZC, Ketha H, McNulty MS, McGee-Lawrence M, Craig TA, Grande JP, Westendorf JJ, Singh RJ, Kumar R (2013) Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium. PNAS 110:6199–6204

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Gaudio A, Pennisi P, Bratengeier C, Torrisi V, Lindner B, Mangiafico RA, Pulvirenti I, Hawa G, Tringali G, Fiore CE (2010) Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab 95:2248–2253

    CAS  PubMed  Google Scholar 

  83. Semenov M, Tamai K, He X (2005) SOST is a ligand for LRP5/LRP6 and a WNT signaling inhibitor. J Biol Chem 280:26770–26775

    CAS  PubMed  Google Scholar 

  84. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–197887

    CAS  PubMed  Google Scholar 

  85. Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R (2006) Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Miner Res 21:1738–1749

    CAS  PubMed  Google Scholar 

  86. Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJJ, van Bezooijen RL, Hatsell S, Economides AN, Mueller TD, Löwik CW, ten Dijke P (2010) Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. J Biol Chem 285:41614–41626

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Sutherland MK, Geoghegan JC, Yu C, Winkler DG, Latham JA (2004) Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts. Bone 35:448–454

    CAS  PubMed  Google Scholar 

  88. Moester MJC, Papapoulos SE, Lowik CW, van Bezooijen RL (2010) Sclerostin: current knowledge and future perspectives. Calcif Tissue Int 87:99–107

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH (2006) The Wnt co-receptor Lrp5 is essential for skeletal mechanotransduction, but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem 281:23698–23711

    CAS  PubMed  Google Scholar 

  90. Galea GL, Sunters A, Meakin LB, Zaman G, Sugiyama T, Lanyon LE, Price JS (2011) Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4. FEBS Lett 585:2450–2454

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Sapir-Koren R, Livshits G (2013) Is interaction between age-dependent decline in mechanical stimulation and osteocyte–estrogen receptor levels the culprit for postmenopausal-impaired bone formation? Osteoporos Int 24:1771–1789

    CAS  PubMed  Google Scholar 

  92. 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 (2008) Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135:825–837

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu QT, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588

    CAS  PubMed  Google Scholar 

  94. Tian X, Setterberg RB, Li X, Paszty C, Ke HZ, Jee WS (2010) Treatment with a sclerostin antibody increases cancellous bone formation and bone mass regardless of marrow composition in adult female rats. Bone 47:529–533

    CAS  PubMed  Google Scholar 

  95. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM, Atkins GJ (2011) Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One 6:e25900

    CAS  PubMed Central  PubMed  Google Scholar 

  96. You L, Temiyasathit S, Lee P, Kim CH, Tummala P, Yao W, Kingery W, Malone AM, Kwon RY, Jacobs CR (2008) Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading. Bone 42:172–179

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Kogawa M, Wijenayaka AR, Ormsby R, Thomas GP, Anderson PH, Bonewald LF, Findlay DM, Atkins JF (2013) Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. J Bone Miner Res 28:2436–2448

    CAS  PubMed  Google Scholar 

  98. Ito N, Findlay DM, Anderson PH, Bonewald LF, Atkins GJ (2013) Extracellular phosphate modulates the effect of 1α,25-dihydroxy vitamin D3 (1,25D) on osteocyte like cells. J Steroid Biochem Mol Biol 136:183–186

    CAS  PubMed  Google Scholar 

  99. Zhou X, Cui Y, Zhou X, Han J (2012) Phosphate/pyrophosphate and MV-related proteins in mineralization: discoveries from mouse models. Int J Biol Sci 8:778–790

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Camalier CE, Yi M, Yu LR, Hood BL, Conrads KA, Lee YJ, Lin Y, Garneys LM, Bouloux GF, Young MR, Veenstra TD, Stephens RM, Colburn NH, Conrads TP, Beck GR Jr (2013) An integrated understanding of the physiological response to elevated extracellular phosphate. J Cell Physiol 228:1536–1550

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Rendenbach C, Yorgan TA, Heckt T, Otto B, Baldauf C, Jeschke A, Streichert T, David JP, Amling M, Schinke T (2014) Effects of extracellular phosphate on gene expression in murine osteoblasts. Calcif Tissue Int 94:473–483

    Google Scholar 

  102. Gluhak-Heinrich J, Ye L, Bonewald LF, Feng JQ, MacDougall M, Harris SE, Pavlin D (2003) Mechanical loading stimulates dentin matrix protein 1 (DMP1) expression in osteocytes in vivo. J Bone Miner Res 18:807–817

    CAS  PubMed  Google Scholar 

  103. Yang W, Lu Y, Kalajzic I, Guo D, Harris MA, Gluhak-Heinrich J, Kotha S, Bonewald LF, Feng JQ, Rowe DW, Turner CH, Robling AG, Harris SE (2005) Dentin matrix protein 1 gene cis regulation: use in osteocytes to characterize local responses to mechanical loading in vitro and in vivo. J Biol Chem 280:20680–20690

    CAS  PubMed  Google Scholar 

  104. Harris SE, Gluhak-Heinrich J, Harris MA, Yang W, Bonewald LF, Riha D, Rowe PSN, Robling AG, Turner CH, Feng JQ, McKee MD, Nicollela D (2007) DMP1 and MEPE expression are elevated in osteocytes after mechanical loading in vivo: theoretical role in controlling mineral quality in the perilacunar matrix. J Musculoskelet Neuronal Interact 7:313–315

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Addison WN, Nakano Y, Loisel T, Crine P, McKee MD (2008) MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res 23:1638–1649

    CAS  PubMed  Google Scholar 

  106. Kulkarni RN, Bakker AD, Everts V, Klein-Nulend J (2010) Inhibition of osteoclastogenesis by mechanically loaded osteocytes: involvement of MEPE. Calcif Tissue Int 87:461–468

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Atkins JG, Rowe PS, Lim HP, Welldon KJ, Ormsby R, Wijenayaka AR, Zelenchuk L, Evdokiou A, Findlay DM (2011) Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Miner Res 26:1425–1436

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Mackenzie NCW, Zhu D, Milne EM, van’t Hof R, Martin A, Quarles DL, Millán JL, Farquharson C, MacRae VE (2012) Altered bone development and an increase in FGF-23 expression in Enpp1 (−/−) mice. PLoS ONE 7:e32177

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Ärnlöv J, Carlsson AC, Sundström J, Ingelsson E, Larsson A, Lind L, Larsson TE (2013) Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int 83:160–166

    PubMed  Google Scholar 

  110. Fang Y, Ginsberg C, Sugatani T, Monier-Faugere MC, Malluche H, Hruska KA (2014) Early chronic kidney disease–mineral bone disorder stimulates vascular calcification. Kidney Int 85:142–150

    CAS  PubMed  Google Scholar 

  111. Lau KH, Baylink DJ, Zhou XD, Rodriguez D, Bonewald LF, Li Z, Ruffoni D, Müller R, Kesavan C, Sheng MH (2013) Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity. Am J Physiol Endocrinol Metab 305:E271–E281

    CAS  PubMed  Google Scholar 

  112. Cohen-Kfir E, Artsi H, Levin A, Abramowitz E, Bajayo A, Gurt I, Zhong L, D’Urso A, Toiber D, Mostoslavsky R, Dresner-Pollak R (2011) Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor. Endocrinology 152:4514–4524

    CAS  PubMed  Google Scholar 

  113. Ohyama Y, Nifuji A, Maeda Y, Amagasa T, Noda M (2004) Spaciotemporal association and bone morphogenetic protein regulation of sclerostin and osterix expression during embryonic osteogenesis. Endocrinology 145:4685–4692

    CAS  PubMed  Google Scholar 

  114. Milat F, Ng KW (2009) Is Wnt signalling the final common pathway leading to bone formation? Mol Cell Endocrinol 310:52–62

    CAS  PubMed  Google Scholar 

  115. van Bezooijen RL, Papapoulos S, Hamdy AT, Lowik CW (2008) SOST/sclerosin: an osteocyte-derived inhibitor of bone formation that antagonizes canonical Wnt signaling. In: Bilezikian JP, Raisz LG, Martin TJ (eds) Principles of bone biology. Academic, San Diego, pp 139–152

    Google Scholar 

  116. Lloyd SA, Loiselle AE, Zhang Y, Donahue HJ (2013) Connexin 43 deficiency desensitizes bone to the effects of mechanical unloading through modulation of both arms of bone remodeling. Bone 57:76–83

    CAS  PubMed  Google Scholar 

  117. Kramer I, Loots GG, Studer A, Keller H, Kneissel M (2010) Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res 25:178–189

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Guo J, Liu M, Yang D, Bouxsein ML, Saito H, Galvin RJ, Kuhstoss SA, Thomas CC, Schipani E, Baron R, Bringhurst FR, Kronenberg HM (2010) Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab 11:161–171

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Powell WF Jr, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, Pajevic PD (2011) Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol 209:21–32

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Mirza FS, Padhi ID, Raisz LG, Lorenzo JA (2010) Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 95:1991–1997

    PubMed Central  PubMed  Google Scholar 

  121. Modder UI, Clowes JA, Hoey K, Peterson JM, McCready L, Oursler MJ, Riggs BL, Khosla S (2011) Regulation of circulating sclerostin levels by sex steroids in women and in men. J Bone Miner Res 26:27–34

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Kim B-J, Bae SJ, Lee S-Y Lee Y-S, Baek J-E, Park S-Y, Lee SH, Koh J-M, Kim GS (2012) TNF-a mediates the stimulation of sclerostin expression in an estrogen-deficient condition. Biochem Biophys Res Commun 424:170–175

    CAS  PubMed  Google Scholar 

  123. Leupin O, Kramer I, Collette NM, Loots GG, Natt F, Kneissel M, Keller H (2007) Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res 22:1957–1967

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Roberts MD, Santner TJ, Hart RT (2009) Local bone formation due to combined mechanical loading and intermittent hPTH-(1-34) treatment and its correlation to mechanical signal distributions. J Biomech 42:2431–2438

    CAS  PubMed  Google Scholar 

  125. Devarajan-Ketha H, Craig TA, Madden BJ, Robert Bergen H 3rd, Kumar R (2012) The sclerostin-bone protein interactome. Biochem Biophys Res Commun 417:830–835

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Lewiecki EM (2014) Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis 6:48–57

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Ominsky MS, Niu QT, Li C, Li X, Ke HZ (2014) Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J Bone Miner Res 29:1424–1430

    CAS  PubMed  Google Scholar 

  128. Ross RD, Edwards LH, Acerbo AS, Ominsky MS, Virdi AS, Sena K, Miller LM, Sumner DR (2014) Bone matrix quality following sclerostin antibody treatment. J Bone Miner Res 29:1597–1607

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was funded by Israel Science Foundation, grant #994/10 and grant #1018/13. The study was also supported by Dr. Herman Showeder fund from the Sackler Faculty of Medicine, Tel Aviv University.

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  1. Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 69978, Israel

    R. Sapir-Koren & G. Livshits

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Sapir-Koren, R., Livshits, G. Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption–formation cycles?. Osteoporos Int 25, 2685–2700 (2014). https://doi.org/10.1007/s00198-014-2808-0

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