Developments in sclerostin biology: Regulation of gene expression, mechanisms of action, and physiological functions

Current Osteoporosis Reports

Volumn 12, Issue 1, 2014, Pages 107-114

  Weivoda, Megan M ^a   Oursler, Merry Jo ^a  

^a MAYO CLINIC   (United States)

Author keywords

LRP; Osteocyte; Osteoporosis; Sclerosteosis; Sclerostin; Skeleton; SOST; Wnt

Indexed keywords

BLOSOZUMAB; BONE MORPHOGENETIC PROTEIN 2; MONOCLONAL ANTIBODY; MYOCYTE ENHANCER FACTOR 2; OSTEOCLAST DIFFERENTIATION FACTOR; PARATHYROID HORMONE; ROMOSOZUMAB; SCLEROSTIN; SCLEROSTIN MONOCLONAL ANTIBODY; SMAD PROTEIN; STROMAL CELL DERIVED FACTOR 1; TRANSCRIPTION FACTOR OSTERIX; TRANSCRIPTION FACTOR RUNX2; UNCLASSIFIED DRUG;

BINDING SITE; BONE DENSITY; BONE MASS; BONE METABOLISM; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; DOWN REGULATION; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG RESPONSE; DRUG TOLERABILITY; GENE; GENE DELETION; GENE EXPRESSION REGULATION; GENE TARGETING; HUMAN; NONHUMAN; OSSIFICATION; OSTEOBLAST; OSTEOCLAST; OSTEOCYTE; OSTEOLYSIS; PHENOTYPE; PROMOTER REGION; PROTEIN BINDING; PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN METHYLATION; PROTEIN PHOSPHORYLATION; REVIEW; SOST GENE;

ANIMALS; BONE DENSITY; BONE MORPHOGENETIC PROTEINS; GENE EXPRESSION REGULATION; GENETIC MARKERS; HUMANS; LDL-RECEPTOR RELATED PROTEINS; SIGNAL TRANSDUCTION; WNT SIGNALING PATHWAY;

EID: 84895925109     PISSN: 15441873     EISSN: 15442241     Source Type: Journal    
DOI: 10.1007/s11914-014-0188-1     Document Type: Review

References (70)

1. van Bezooijen R, ten Dijke P, Papapoulos SE, Lowik CW. SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev. 2005;16:319-27. (Pubitemid 40910321)
2. van Hul W, Balemans W, van Hul E, Dikkers F, Obee H, Stokroos R, et al. van Buchem Disease (hyperostosis corticalis generalisata) maps to the chromosome 17q12-q21. Am J Hum Genet. 1998;62:391-9. (Pubitemid 28110782)
3. Balemans W, Van Den Ende J, Freire Paes-Alves A, Dikkers FG, Willems PJ, Vanhoenacker F, et al. Localization of the Gene for Sclerosteosis to the van Buchem Disease-Gene Region on Chromosome 17q12-q21. Am J Hum Genet. 1999;64:1661-9. (Pubitemid 30481518)
4. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Molec Genet. 2001;10(5):537-43. (Pubitemid 32184286)
5. Brunkow M, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68:577-89. (Pubitemid 32202753)
6. • van Lierop A, Hamdy NAT, Hamersma H, van Bezooijen RL, Power J, Loveridge N, et al. Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. J Bone Miner Res. 2011;26(12):2804-11. This manuscript provides evidence that decreased or absent sclerostin leads to increased bone mass in humans. Importantly, decreased sclerostin in sclerosteosis carriers correlated with increased bone mass without disease symptoms.
7. Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002;39:91-7. (Pubitemid 34146376)
8. • van Lierop A, Hamdy NAT, van Egmond ME, Bakker E, Dikkers FG, Papapoulos SE. Van Buchem Disease: clinical, biochemical, and densitometric features of patients and disease carriers. J Bone Miner Res. 2013;28(4):848-54. This manuscript provides evidence that there is a gene-dose effect of the VBD mutation on circulating sclerostin, suggesting that altered sclerostin levels affects the severity of the bone phenotype in VBD and sclerosteosis patients.
9. Burgers T, Williams BO. Regulation of Wnt/β-catenin signaling within and from osteocytes. Bone. 2013;54:244-9.
10. Rossini M, Gatti D, Adami S. Involvement of WNT/β-catenin Signaling in the treatment of osteoporosis. Calcif Tissue Int. 2013;93:121-32.
11. Little R, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70:11-9. (Pubitemid 34031693)
12. Boyden L, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346:1513-21. (Pubitemid 34755690)
13. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, et al. 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. (Pubitemid 33152786)
14. Ott S. Editorial: sclerostin and Wnt signaling - the pathway to bone strength. J Clin Endo Metab. 2005;90(12):6741-3. (Pubitemid 41759344)
15. Ohyama Y, Nifuji A, Maeda Y, Amagasa T, Noda M. Spaciotemporal association and bone morphogenetic protein regulation of sclerostin and osterix expression during embryonic osteogenesis. Endocrinology. 2004;145(10):4685-92. doi:10.1210/en.2003-1492. (Pubitemid 39281462)
16. van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004;199(6):805-14. doi:10.1084/jem.20031454. (Pubitemid 38375200)
17. Van Bezooijen R, Bronckers A, Gortzak R, Hogendoorn P, van der Wee-Pals L, Balemans W, et al. Sclerostin in mineralized matrices and van Buchem disease. J Dental Res. 2009;88(6):569-74.
18. Moester M, Papapoulos SE, Lowik CWGM, van Bezooijen RL. Sclerostin: current knowledge and future perspectives. Calcif Tissue Int. 2010;87:99-107.
19. Kusu N, Laurikkala J, Imanishi M, Usui H, Konishi M, Miyake A, et al. Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem. 2003;278(26):24113-7. doi:10.1074/jbc.M301716200. (Pubitemid 36830246)
20. Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci U S A. 2008;105(52):20764-9. doi:10.1073/pnas.0805133106.
21. Ota K, Quint P, Ruan M, Pederson L, Westendorf JJ, Khosla S, et al. Sclerostin is expressed in osteoclasts from aged mice and reduces osteoclast-mediated stimulation of mineralization. J Cell Biochem. 2013;114(8):1901-7. doi:10.1002/jcb.24537.
22. Tang W, Li Y, Osimiri L, Zhang C. Osteoblast-specific Transcription Factor Osterix (Osx) is an upstream regulator of Satb2 during bone formation. J Biol Chem. 2011;286(38):32995-3002. doi:10.1074/jbc.M111.244236.
23. Sevetson B, Taylor S, Pan Y. Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST). J Biol Chem. 2004;279(14):13849-58. doi:10.1074/jbc.M306249200. (Pubitemid 38468917)
24. Yang F, Tang W, So S, de Crombrugghe B, Zhang C. Sclerostin is a direct target of osteoblast-specific transcription factor osterix. Biochem Biophys Res Commun. 2010;400(4):684-8. doi:10.1016/j.bbrc.2010.08.128.
25. • Delgado-Calle J, Sanudo C, Bolado A, Fernandez AF, Arozamena J, Pascual-Carra MA, et al. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J Bone Min Res. 2012;27(4):926-37. doi:10.1002/jbmr.1491. These data show that epigenetics contributes to the regulation of sclerostin expression.
26. •• Delgado-Calle J, Arozamena J, Perez-Lopez J, Bolado-Carrancio A, Sanudo C, Agudo G, et al. Role of BMPs in the regulation of sclerostin as revealed by an epigenetic modifier of human bone cells. Mol Cell Endocrinol. 2013;369(1-2):27-34. doi:10.1016/j.mce.2013.02.002. These data demonstrate that epigenetic modulation of the sclerostin promoter contributes to the ability microenvironment factors to affect sclerostin expression.
27. Kamiya N, Ye L, Kobayashi T, Mochida Y, Yamauchi M, Kronenberg HM, et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development. 2008;135(22):3801-11. doi:10.1242/dev.025825.
28. Papanicolaou SE, Phipps RJ, Fyhrie DP, Genetos DC. Modulation of sclerostin expression by mechanical loading and bone morphogenetic proteins in osteogenic cells. Biorheology. 2009;46(5):389-99. doi:10.3233/BIR-2009-0550.
29. •• Collette NM, Genetos DC, Economides AN, Xie L, Shahnazari M, Yao W, et al. Targeted deletion of SOST distal enhancer increases bone formation and bone mass. Proc Natl Acad Sci U S A. 2012;109(35):14092-7. doi:10.1073/pnas.1207188109. Deletion of the ECR5 enhancer region causes a bone phenotype similar to van Buchem's Disease.
30. Leupin O, Kramer I, Collette NM, Loots GG, Natt F, Kneissel M, et al. Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Min Res. 2007;22(12):1957-67. doi:10.1359/jbmr.070804. (Pubitemid 351229312)
31. Loots GG, Keller H, Leupin O, Murugesh D, Collette NM, Genetos DC. TGF-beta regulates sclerostin expression via the ECR5 enhancer. Bone. 2012;50(3):663-9. doi:10.1016/j.bone.2011.11.016.
32. Quinn ZA, Yang CC, Wrana JL, McDermott JC. Smad proteins function as co-modulators for MEF2 transcriptional regulatory proteins. Nucleic Acids Res. 2001;29(3):732-42. (Pubitemid 32124385)
33. Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone. 2005;37(2):148-58. doi:10.1016/j.bone.2005.03.018. (Pubitemid 40962421)
34. Genetos DC, Yellowley CE, Loots GG. Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression. PLoS One. 2011;6(3):e17772. doi:10.1371/journal.pone.0017772.
35. Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, et al. Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Min Res. 2006;21(11):1738-49. doi:10.1359/jbmr.060810. (Pubitemid 46141229)
36. Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, Muskett FW, et al. Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. J Biol Chem. 2009;284(16):10890-900. doi:10.1074/jbc.M807994200.
37. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. Embo J. 2003;22(23):6267-76. doi:10.1093/emboj/cdg599. (Pubitemid 37522584)
38. Collette NM, Genetos DC, Murugesh D, Harland RM, Loots GG. Genetic evidence that SOST inhibits WNT signaling in the limb. Dev Biol. 2010;342(2):169-79. doi:10.1016/j.ydbio.2010.03.021.
39. Itasaki N, Jones CM, Mercurio S, Rowe A, Domingos PM, Smith JC, et al. Wise, a context-dependent activator and inhibitor of Wnt signalling. Development. 2003;130(18):4295-305. (Pubitemid 37185319)
40. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280(20):19883-7. doi:10.1074/jbc.M413274200. (Pubitemid 41379516)
41. • Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286(22):19489-500. doi:10.1074/jbc.M110. 190330. This publication shows that interaction of sclerostin with LRP4 can also contribute to the regulation of human bone metabolism.
42. • Holdsworth G, Slocombe P, Doyle C, Sweeney B, Veverka V, Le Riche K, et al. Characterization of the interaction of sclerostin with the low density lipoprotein receptor-related protein (LRP) family of Wnt co-receptors. J Biol Chem. 2012;287(32):26464-77. doi:10.1074/jbc.M112.350108. These data characterize the binding of sclerostin to LRP.
43. Bourhis E, Wang W, Tam C, Hwang J, Zhang Y, Spittler D, et al. Wnt antagonists bind through a short peptide to the first beta-propeller domain of LRP5/6. Structure. 2011;19(10):1433-42. doi:10.1016/j.str.2011.07.005.
44. Semenov MV, He X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J Biol Chem. 2006;281(50):38276-84. doi:10.1074/jbc.M609509200. (Pubitemid 46043307)
45. Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, et al. Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone. 2004;35(4):828-35. doi:10.1016/j.bone.2004. 05.023. (Pubitemid 39349213)
46. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of SOST/sclerostin. J Biol Chem. 2008;283(9):5866-75. doi:10.1074/jbc.M705092200.
47. •• Tu X, Rhee Y, Condon KW, Bivi N, Allen MR, Dwyer D, et al. SOST downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone. 2012;50(1):209-17. doi:10.1016/j.bone. 2011.10.025. Transgenic SOST expression prevents the loading-induced osteogenic response, demonstrating that the modulation of SOST expression in osteocytes is a mechanism by which mechanical-loading stimulates bone formation.
48. Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, et al. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Min Res. 2009;24(10):1651-61. doi:10.1359/jbmr.090411.
49. Galea GL, Sunters A, Meakin LB, Zaman G, Sugiyama T, Lanyon LE, et al. SOST down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4. FEBS Lett. 2011;585(15):2450-4. doi:10.1016/j.febslet. 2011.06.019.
50. Nguyen J, Tang SY, Nguyen D, Alliston T. Load regulates bone formation and Sclerostin expression through a TGFbeta-dependent mechanism. PLoS One. 2013;8(1):e53813. doi:10.1371/journal.pone.0053813.
51. Lips P, Courpron P, Meunier PJ. Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res. 1978;26(1):13-7. (Pubitemid 9088823)
52. Modder UI, Hoey KA, Amin S, McCready LK, Achenbach SJ, Riggs BL, et al. Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J Bone Min Res. 2011;26(2):373-9. doi:10.1002/jbmr.217.
53. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM, Atkins GJ. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One. 2011;6(10):e25900. doi:10.1371/journal.pone. 0025900.
54. Kogawa M, Wijenayaka AR, Ormsby R, Thomas GP, Anderson PH, Bonewald LF, et al. Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. J Bone Min Res. 2013;28:2436-2448 doi:10.1002/jbmr. 2003.
55. Qiang YW, Chen Y, Brown N, Hu B, Epstein J, Barlogie B, et al. Characterization of Wnt/beta-catenin signalling in osteoclasts in multiple myeloma. Br J Haematol. 2010;148(5):726-38. doi:10.1111/j.1365-2141.2009.08009. x.
56. Ruan M, Pederson L, Hachfeld C, Thomson M, Prakash YS, Howe A, et al. Deletion of Wnt Receptors Lrp5 and Lrp6 or β-catenin in late osteoclast precursors differentially suppress osteoclast differentiation and bone metabolism. J Bone Miner Res. 2012;27(Suppl 1).
57. Wei W, Zeve D, Suh JM, Wang X, Du Y, Zerwekh JE, et al. Biphasic and dosage-dependent regulation of osteoclastogenesis by beta-catenin. Mol Cell Biol. 2011;31(23):4706-19. doi:10.1128/MCB.05980-11.
58. Otero K, Shinohara M, Zhao H, Cella M, Gilfillan S, Colucci A, et al. TREM2 and beta-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis. J Immunol. 2012;188(6):2612-21. doi:10.4049/jimmunol. 1102836.
59. Albers J, Keller J, Baranowsky A, Beil FT, Catala-Lehnen P, Schulze J, et al. Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin. J Cell Biol. 2013;200(4):537-49. doi:10.1083/jcb.201207142.
60. 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 Min Res. 2010;25(2):178-89. doi:10.1359/jbmr.090730.
61. Cain CJ, Rueda R, McLelland B, Collette NM, Loots GG, Manilay JO. Absence of sclerostin adversely affects B-cell survival. J Bone Min Res. 2012;27(7):1451-61. doi:10.1002/jbmr.1608.
62. Brandenburg VM, Kramann R, Koos R, Kruger T, Schurgers L, Muhlenbruch G, et al. Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study. BMC Nephrol. 2013;14:219. doi:10.1186/1471-2369-14-219.
63. Claes KJ, Viaene L, Heye S, Meijers B, d'Haese P, Evenepoel P. Sclerostin: another vascular calcification inhibitor? J Clin Endocrinol Metab. 2013;98(8):3221-8. doi:10.1210/jc.2013-1521.
64. Noordzij M, Cranenburg EM, Engelsman LF, Hermans MM, Boeschoten EW, Brandenburg VM, et al. Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients. Nephrol Dial Transplant. 2011;26(5):1662-9. doi:10.1093/ndt/gfq582.
65. Gardner J, van Bezooijen RL, Mervis B, Hamdy NAT, Lowik CWGM, Hamersma H, et al. Bone mineral density in sclerosteosis: affected individuals and gene carriers. J Clin Endo Metab. 2005;90(12):6392-5. (Pubitemid 41759290)
66. Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Min Res. 2009;24(4):578-88. doi:10.1359/jbmr.081206.
67. Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Min Res. 2010;25(5):948-59. doi:10.1002/jbmr.14.
68. Tian X, Jee WS, Li X, Paszty C, Ke HZ. Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. Bone. 2011;48(2):197-201. doi:10.1016/j.bone.2010.09.009.
69. •• Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Min Res. 2011;26(1):19-26. doi:10.1002/jbmr.173. The first-in-human study assessing the effects of sclerostin monoclonal antibody AMG 785 on the skeleton.
70. •• McColm J, Hu L, Womack T, Tang CC, Chiang AY. Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J Bone Min Res. 2013. doi:10.1002/jbmr.2092. This study assesses the effects of the sclerostin monoclonal antibody blosozumab on the skeleton.