Potential of modulating Wnt signaling pathway toward the development of bone anabolic agent

Current Molecular Pharmacology

Volumn 5, Issue 2, 2012, Pages 164-173

  Krause, Ulf ^a   Gregory, Carl A ^a  

^a TEXAS A AND M HEALTH SCIENCE CENTER   (United States)

Author keywords

Dkk 1; Glycogen synthetase kinase 3 ; Mesenchymal stem progenitor cell; Osteogenic differentiation; Wntsignaling

Indexed keywords

2 CHLORO 5 NITROBENZANILIDE; 6 BROMOINDIRUBIN 3' MONOXIME; ANDROSTANOLONE; ANTISENSE OLIGONUCLEOTIDE; CALCITRIOL; DICKKOPF 1 PROTEIN; DICKKOPF 1 PROTEIN ANTIBODY; DICKKOPF 1 PROTEIN ANTISENSE NUCLEOTIDE; DIPHENYLSULFONYL SULFONAMIDE DERIVATIVE; FORSKOLIN; GLYCOGEN SYNTHASE KINASE 3 INHIBITOR; GLYCOGEN SYNTHASE KINASE 3BETA; INDIRUBIN 3' MONOOXIME; LITHIUM; LITHIUM CHLORIDE; MELATONIN; PARATHYROID HORMONE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROTEIN INHIBITOR; SCLEROSTIN; SECRETED FRIZZLED RELATED PROTEIN 2; UNCLASSIFIED DRUG; WNT INHIBITOR; WNT PROTEIN;

BIPOLAR DISORDER; BONE DENSITY; BONE DESTRUCTION; BONE DEVELOPMENT; BONE DISEASE; BRACHYDACTYLY; DOSE RESPONSE; FRACTURE; GAIN OF FUNCTION MUTATION; HUMAN; LOSS OF FUNCTION MUTATION; MISSENSE MUTATION; NONHUMAN; NONSENSE MUTATION; OSSIFICATION; OSTEOLYSIS; OSTEOPOROSIS; PAGET BONE DISEASE; PRIORITY JOURNAL; REVIEW; ROBINOW SYNDROME; WNT SIGNALING PATHWAY;

EID: 84861733408     PISSN: 18744672     EISSN: 18744702     Source Type: Journal    
DOI: 10.2174/1874467211205020164     Document Type: Review

References (107)

1. Bain, G.; Muller, T.; Wang, X.; Papkoff, J. Activated beta-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction. Biochem. Biophys. Res. Commun., 2003, 301, 84-91.
2. Rawadi, G.; Vayssiere, B.; Dunn, F.; Baron, R.; Roman-Roman, S. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J. Bone Miner. Res., 2003, 18, 1842-1853.
3. Gregory, C.A.; Green, A.; Lee, N.; Rao, A.; Gunn, W. The promise of canonical Wnt signaling modulators in enhancing bone repair. Drug News Perspect., 2006, 19, 445-452.
4. Huelsken, J. and Birchmeier, W. New aspects of Wnt signaling pathways in higher vertebrates. Curr. Opin. Genet. Dev., 2001, 11, 547-553.
5. Pandur, P.; Maurus, D.; Kuhl, M. Increasingly complex: new players enter the Wnt signaling network. Bioessays, 2002, 24, 881-884.
6. Cadigan, K.M.; Nusse, R. Wnt signaling: a common theme in animal development. Genes Dev., 1997, 11, 3286-3305.
7. Glass, D.A. 2nd; Karsenty, G. In vivo analysis of Wnt signaling in bone. Endocrinology, 2007, 148, 2630-2634.
8. Williams, B.O. and Insogna, K.L. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J. Bone Miner. Res., 2009, 24, 171-178.
9. Willert, K.; Brown, J.D.; Danenberg, E.; Duncan, A.W.; Weissman, I.L.; Reya, T.; Yates, J.R. 3rd; Nusse, R. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature, 2003, 423, 448-452.
10. Burrus, L.W. Wnt-1 as a short-range signaling molecule. Bioessays, 1994, 16, 155-157.
11. Logan, C.Y.; Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol., 2004, 20, 781-810.
12. Christian, J.L. BMP, Wnt and Hedgehog signals: how far can they go? Curr. Opin. Cell Biol., 2000, 12, 244-249.
13. Tian, E.; Zhan, F.; Walker, R.; Rasmussen, E.; Ma, Y.; Barlogie, B.; Shaughnessy, J.D. Jr. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med., 2003, 349, 2483-2494.
14. Aslan, H.; Ravid-Amir, O.; Clancy, B.M.; Rezvankhah, S.; Pittman, D.; Pelled, G.; Turgeman, G.; Zilberman, Y.; Gazit, Z.; Hoffmann, A.; Gross, G.; Domany, E.; Gazit, D. Advanced molecular profiling in vivo detects novel function of dickkopf-3 in the regulation of bone formation. J. Bone Miner. Res., 2006, 21, 1935-1945.
15. Kawano, Y. and Kypta, R. Secreted antagonists of the Wnt signalling pathway. J. Cell Sci., 2003, 116, 2627-2634.
16. Bennett, C.N.; Longo, K.A.; Wright, W.S.; Suva, L.J.; Lane, T.F.; Hankenson, K.D.; MacDougald, O.A. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc. Natl. Acad. Sci. USA, 2005, 102, 3324-3329.
17. Bennett, C.N.; Ouyang, H.; Ma, Y.L.; Zeng, Q.; Gerin, I.; Sousa, K.M.; Lane, T.F.; Krishnan, V.; Hankenson, K.D.; MacDougald, O.A. Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J. Bone Miner. Res., 2007, 22, 1924-1932.
18. Stevens, J.R.; Miranda-Carboni, G.A.; Singer, M.A.; Brugger, S.M.; Lyons, K.M.; Lane, T.F. Wnt10b deficiency results in agedependent loss of bone mass and progressive reduction of mesenchymal progenitor cells. J. Bone Miner. Res., 2010, 25, 2138-2147.
19. Holmen, S.L.; Zylstra, C.R.; Mukherjee, A.; Sigler, R.E.; Faugere, M.C.; Bouxsein, M.L.; Deng, L.; Clemens, T.L.; Williams, B.O. Essential role of beta-catenin in postnatal bone acquisition. J. Biol. Chem., 2005, 280, 21162-21168.
20. Chen, Y.; Whetstone, H.C.; Lin, A.C.; Nadesan, P.; Wei, Q.; Poon, R.; Alman, B.A. Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Med., 2007, 4, e249
21. Bodine, P.V.; Zhao, W.; Kharode, Y.P.; Bex, F.J.; Lambert, A.J.; Goad, M.B.; Gaur, T.; Stein, G.S.; Lian, J.B.; Komm, B.S. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol. Endocrinol., 2004, 18, 1222-1237
22. Morvan, F.; Boulukos, K.; Clement-Lacroix, P.; Roman Roman, S.; Suc-Royer, I.; Vayssiere, B.; Ammann, P.; Martin, P.; Pinho, S.; Pognonec, P.; Mollat, P.; Niehrs, C.; Baron, R.; Rawadi, G. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J. Bone Miner. Res., 2006, 21, 934-945.
23. MacDonald, B.T.; Joiner, D.M.; Oyserman, S.M.; Sharma, P.; Goldstein, S.A.; He, X.; Hauschka, P.V. Bone mass is inversely proportional to Dkk1 levels in mice. Bone, 2007, 41, 331-339.
24. Witte, F.; Dokas, J.; Neuendorf, F.; Mundlos, S.; Stricker, S. Comprehensive expression analysis of all Wnt genes and their major secreted antagonists during mouse limb development and cartilage differentiation. Gene Expr. Patterns, 2009, 9, 215-223.
25. Semenov, M.V.; Habas, R.; Macdonald, B.T.; He, X. SnapShot: Noncanonical Wnt Signaling Pathways. Cell, 2007, 131, 1378.
26. Tu, X.; Joeng, K.S.; Nakayama, K.I.; Nakayama, K.; Rajagopal, J.; Carroll, T.J.; McMahon, A.P.; Long, F. Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation. Dev Cell, 2007, 12, 113-127.
27. Wang, B.; Sinha, T.; Jiao, K.; Serra, R.; Wang, J. Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B. Hum. Mol. Genet., 2011, 20(2), 271-285.
28. Baksh, D.; Tuan, R.S. Canonical and non-canonical Wnts differentially affect the development potential of primary isolate of human bone marrow mesenchymal stem cells. J. Cell. Physiol., 2007, 212, 817-826.
29. Boland, G.M.; Perkins, G.; Hall, D.J.; Tuan, R.S. Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J. Cell. Biochem., 2004, 93, 1210-1230.
30. Shi, Y.C.; Worton, L.; Esteban, L.; Baldock, P.; Fong, C.; Eisman, J.A.; Gardiner, E.M. Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic proliferation and differentiation. Bone, 2007, 41, 87-96.
31. Quarto, N.; Behr, B.; Longaker, M.T. Opposite Spectrum of Activity of Canonical Wnt Signaling in the Osteogenic Context of Undifferentiated and Differentiated Mesenchymal Cells: Implications for Tissue Engineering. Tissue Eng. Part A, 2010, 16(10), 3185-3197.
32. Santos, A.; Bakker, A.D.; Blieck-Hogervorst, J.M.; Klein-Nulend, J. WNT5A induces osteogenic differentiation of human adipose stem cells via rho-associated kinase Rock. Cytotherapy, 2010, 12(7), 924-932.
33. Chang, J.; Sonoyama, W.; Wang, Z.; Jin, Q.; Zhang, C.; Krebsbach, P.H.; Giannobile, W.; Shi, S.; Wang, C.Y. Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J. Biol. Chem., 2007, 282, 30938-30948.
34. Gong, Y.; Slee, R.B.; Fukai, N.; Rawadi, G.; Roman-Roman, S.; Reginato, A.M.; Wang, H.; Cundy, T.; Glorieux, F.H.; Lev, D.; Zacharin, M.; Oexle, K.; Marcelino, J.; Suwairi, W.; Heeger, S.; Sabatakos, G.; Apte, S.; Adkins, W.N.; Allgrove, J.; Arslan-Kirchner, M.; Batch, J.A.; Beighton, P.; Black, G.C.; Boles, R.G.; Boon, L.M.; Borrone, C.; Brunner, H.G.; Carle, G.F.; Dallapiccola, B.; De Paepe, A.; Floege, B.; Halfhide, M.L.; Hall, B.; Hennekam, R.C.; Hirose, T.; Jans, A.; Juppner, H.; Kim, C.A.; Keppler-Noreuil, K.; Kohlschuetter, A.; LaCombe, D.; Lambert, M.; Lemyre, E.; Letteboer, T.; Peltonen, L.; Ramesar, R.S.; Romanengo, M.; Somer, H.; Steichen-Gersdorf, E.; Steinmann, B.; Sullivan, B.; Superti-Furga, A.; Swoboda, W.; van den Boogaard, M.J.; Van Hul, W.; Vikkula, M.; Votruba, M.; Zabel, B.; Garcia, T.; Baron, R.; Olsen, B.R.; Warman, M.L. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell, 2001, 107, 513-523.
35. Boyden, L.M.; Mao, J.; Belsky, J.; Mitzner, L.; Farhi, A.; Mitnick, M.A.; Wu, D.; Insogna, K.; Lifton, R.P. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med., 2002, 346, 1513-1521.
36. Balemans, W.; Devogelaer, J.P.; Cleiren, E.; Piters, E.; Caussin, E.; Van Hul, W. Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling. J. Bone Miner. Res., 2007, 22, 708-716.
37. Qiu, W.; Andersen, T.E.; Bollerslev, J.; Mandrup, S.; Abdallah, B.M.; Kassem, M. Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells. J. Bone Miner. Res., 2007, 22, 1720-1731.
38. Mason, J.J.; Williams, B.O. SOST and DKK: Antagonists of LRP Family Signaling as Targets for Treating Bone Disease. J. Osteoporos., 2010, pii: 460120.
39. Piters, E.; Culha, C.; Moester, M.; Van Bezooijen, R.; Adriaensen, D.; Mueller, T.; Weidauer, S.; Jennes, K.; de Freitas, F.; Lowik, C.; Timmermans, J.P.; Van Hul, W.; Papapoulos, S. First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function. Hum. Mutat., 2010, 31, E1526-1543.
40. Li, X.; Ominsky, M.S.; Warmington, K.S.; Morony, S.; Gong, J.; Cao, J.; Gao, Y.; Shalhoub, V.; Tipton, B.; Haldankar, R.; Chen, Q.; Winters, A.; Boone, T.; Geng, Z.; Niu, Q.T.; Ke, H.Z.; Kostenuik, P.J.; Simonet, W.S.; Lacey, D.L.; Paszty, C. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res., 2009, 24, 578-588.
41. Zhou, H.; Mak, W.; Kalak, R.; Street, J.; Fong-Yee, C.; Zheng, Y.; Dunstan, C.R.; Seibel, M.J. Glucocorticoid-dependent Wnt signaling by mature osteoblasts is a key regulator of cranial skeletal development in mice. Development, 2009, 136, 427-436.
42. Weng, L.H.; Wang, C.J.; Ko, J.Y.; Sun, Y.C.; Su, Y.S.; Wang, F.S. Inflammation induction of Dickkopf-1 mediates chondrocyte apoptosis in osteoarthritic joint. Osteoarthritis Cartilage, 2009, 17, 933-943.
43. Diarra, D.; Stolina, M.; Polzer, K.; Zwerina, J.; Ominsky, M.S.; Dwyer, D.; Korb, A.; Smolen, J.; Hoffmann, M.; Scheinecker, C.; van der Heide, D.; Landewe, R.; Lacey, D.; Richards, W.G.; Schett, G. Dickkopf-1 is a master regulator of joint remodeling. Nat. Med., 2007, 13, 156-163.
44. Weng, L.H.; Wang, C.J.; Ko, J.Y.; Sun, Y.C.; Wang, F.S. Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis Rheum., 2010, 62, 1393-1402.
45. Oshima, T.; Abe, M.; Asano, J.; Hara, T.; Kitazoe, K.; Sekimoto, E.; Tanaka, Y.; Shibata, H.; Hashimoto, T.; Ozaki, S.; Kido, S.; Inoue, D.; Matsumoto, T. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood, 2005, 106, 3160-3165.
46. Gunn, W.G.; Conley, A.; Deininger, L.; Olson, S.D.; Prockop, D.J.; Gregory, C.A. A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells, 2006, 24, 986-991.
47. Bueno, C.; Lopes, L.F.; Menendez, P. Bone marrow stromal cellderived Wnt signals as a potential underlying mechanism for cyclin D1 deregulation in multiple myeloma lacking t(11;14)(q13;q32). Blood Cells Mol. Dis., 2007, 39, 366-368.
48. Chim, C.S.; Pang, R.; Fung, T.K.; Choi, C.L.; Liang, R. Epigenetic dysregulation of Wnt signaling pathway in multiple myeloma. Leukemia, 2007, 21, 2527-2536.
49. Colla, S.; Zhan, F.; Xiong, W.; Wu, X.; Xu, H.; Stephens, O.; Yaccoby, S.; Epstein, J.; Barlogie, B.; Shaughnessy, J.D., Jr. The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells. Blood, 2007, 109, 4470-4477.
50. Kobune, M.; Chiba, H.; Kato, J.; Kato, K.; Nakamura, K.; Kawano, Y.; Takada, K.; Takimoto, R.; Takayama, T.; Hamada, H.; Niitsu, Y. Wnt3/RhoA/ROCK signaling pathway is involved in adhesionmediated drug resistance of multiple myeloma in an autocrine mechanism. Mol. Cancer Ther., 2007, 6, 1774-1784.
51. Sukhdeo, K.; Mani, M.; Zhang, Y.; Dutta, J.; Yasui, H.; Rooney, M.D.; Carrasco, D.E.; Zheng, M.; He, H.; Tai, Y.T.; Mitsiades, C.; Anderson, K.C.; Carrasco, D.R. Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc. Natl. Acad. Sci. USA, 2007, 104, 7516-7521.
52. Yaccoby, S.; Ling, W.; Zhan, F.; Walker, R.; Barlogie, B.; Shaughnessy, J.D., Jr. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood, 2007, 109, 2106-2111.
53. Edwards, C.M.; Edwards, J.R.; Lwin, S.T.; Esparza, J.; Oyajobi, B.O.; McCluskey, B.; Munoz, S.; Grubbs, B.; Mundy, G.R. Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood, 2008, 111, 2833-2842.
54. Qiang, Y.W.; Barlogie, B.; Rudikoff, S.; Shaughnessy, J.D., Jr. Dkk1-induced inhibition of Wnt signaling in osteoblast differentiation is an underlying mechanism of bone loss in multiple myeloma. Bone, 2008, 42, 669-680.
55. Qiang, Y.W.; Chen, Y.; Stephens, O.; Brown, N.; Chen, B.; Epstein, J.; Barlogie, B.; Shaughnessy, J.D., Jr. Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood, 2008, 112, 196-207.
56. Zhou, Y.; Uddin, S.; Zimmerman, T.; Kang, J.A.; Ulaszek, J.; Wickrema, A. Growth control of multiple myeloma cells through inhibition of glycogen synthase kinase-3. Leuk. Lymphoma, 2008, 49, 1945-1953.
57. Jost, E.; Gezer, D.; Wilop, S.; Suzuki, H.; Herman, J.G.; Osieka, R.; Galm, O. Epigenetic dysregulation of secreted Frizzled-related proteins in multiple myeloma. Cancer Lett., 2009, 281, 24-31.
58. Lee, N.; Smolarz, A.J.; Olson, S.; David, O.; Reiser, J.; Kutner, R.; Daw, N.C.; Prockop, D.J.; Horwitz, E.M.; Gregory, C.A. A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies. Br. J. Cancer, 2007, 97, 1552-1559.
59. Hall, C.L.; Daignault, S.D.; Shah, R.B.; Pienta, K.J.; Keller, E.T. Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis. Prostate, 2008, 68, 1396-1404.
60. Voorzanger-Rousselot, N.; Goehrig, D.; Journe, F.; Doriath, V.; Body, J.J.; Clezardin, P.; Garnero, P. Increased Dickkopf-1 expression in breast cancer bone metastases. Br. J. Cancer, 2007, 97, 964-970.
61. Cai, Y.; Mohseny, A.B.; Karperien, M.; Hogendoorn, P.C.; Zhou, G.; Cleton-Jansen, A.M. Inactive Wnt/beta-catenin pathway in conventional high-grade osteosarcoma. J. Pathol., 2010, 220, 24-33.
62. McCarthy, H.S. and Marshall, M.J. Dickkopf-1 as a potential therapeutic target in Paget's disease of bone. Expert Opin. Ther. Targets, 2010, 14, 221-230.
63. Marshall, M.J.; Evans, S.F.; Sharp, C.A.; Powell, D.E.; McCarthy, H.S.; Davie, M.W. Increased circulating Dickkopf-1 in Paget's disease of bone. Clin. Biochem., 2009, 42, 965-969.
64. Naot, D.; Bava, U.; Matthews, B.; Callon, K.E.; Gamble, G.D.; Black, M.; Song, S.; Pitto, R.P.; Cundy, T.; Cornish, J.; Reid, I.R. Differential gene expression in cultured osteoblasts and bone marrow stromal cells from patients with Paget's disease of bone. J. Bone Miner. Res., 2007, 22, 298-309.
65. Bajada, S.; Marshall, M.J.; Wright, K.T.; Richardson, J.B.; Johnson, W.E. Decreased osteogenesis, increased cell senescence and elevated Dickkopf-1 secretion in human fracture non union stromal cells. Bone, 2009, 45, 726-735.
66. Hofmann, A.; Ritz, U.; Hessmann, M.H.; Schmid, C.; Tresch, A.; Rompe, J.D.; Meurer, A.; Rommens, P.M. Cell viability, osteoblast differentiation, and gene expression are altered in human osteoblasts from hypertrophic fracture non-unions. Bone, 2008, 42, 894-906.
67. Kulkarni, N.H.; Onyia, J.E.; Zeng, Q.; Tian, X.; Liu, M.; Halladay, D.L.; Frolik, C.A.; Engler, T.; Wei, T.; Kriauciunas, A.; Martin, T.J.; Sato, M.; Bryant, H.U.; Ma, Y.L. Orally bioavailable GSK-3alpha/beta dual inhibitor increases markers of cellular differentiation in vitro and bone mass in vivo. J. Bone Miner. Res., 2006, 21, 910-920.
68. Clement-Lacroix, P.; Ai, M.; Morvan, F.; Roman-Roman, S.; Vayssiere, B.; Belleville, C.; Estrera, K.; Warman, M.L.; Baron, R.; Rawadi, G. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc. Natl. Acad. Sci. USA, 2005, 102, 17406-17411.
69. Li, J.; Sarosi, I.; Cattley, R.C.; Pretorius, J.; Asuncion, F.; Grisanti, M.; Morony, S.; Adamu, S.; Geng, Z.; Qiu, W.; Kostenuik, P.; Lacey, D.L.; Simonet, W.S.; Bolon, B.; Qian, X.; Shalhoub, V.; Ominsky, M.S.; Zhu Ke, H.; Li, X.; Richards, W.G. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone, 2006, 39, 754-766.
70. Derksen, P.W.; Tjin, E.; Meijer, H.P.; Klok, M.D.; MacGillavry, H.D.; van Oers, M.H.; Lokhorst, H.M.; Bloem, A.C.; Clevers, H.; Nusse, R.; van der Neut, R.; Spaargaren, M.; Pals, S.T. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc. Natl. Acad. Sci. USA, 2004, 101, 6122-6127.
71. Chebel, A.; Kagialis-Girard, S.; Catallo, R.; Chien, W.W.; Mialou, V.; Domenech, C.; Badiou, C.; Tigaud, I.; Ffrench, M. Indirubin derivatives inhibit malignant lymphoid cell proliferation. Leuk. Lymphoma, 2009, 50, 2049-2060.
72. Damiens, E.; Baratte, B.; Marie, D.; Eisenbrand, G.; Meijer, L. Anti-mitotic properties of indirubin-3'-monoxime, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest. Oncogene, 2001, 20, 3786-3797.
73. Krause, U.; Harris, S.; Green, A.; Ylostalo, J.; Zeitouni, S.; Lee, N.; Gregory, C.A. Pharmaceutical modulation of canonical Wnt signaling in multipotent stromal cells for improved osteoinductive therapy. Proc. Natl. Acad. Sci. USA, 2010, 107, 4147-4152.
74. Gunn, W.G.; Krause, U.; Lee, N.; Gregory, C.A. Pharmaceutical inhibition of glycogen-synthetase-kinase-3-beta reduces multiple myeloma-induced bone disease in a novel murine plasmacytoma xenograft model. Blood, 2011, 117(5), 1641-1651.
75. Vestergaard, P.; Rejnmark, L.; Mosekilde, L. Reduced relative risk of fractures among users of lithium. Calcif. Tissue Int., 2005, 77, 1-8.
76. Natsume, H.; Tokuda, H.; Adachi, S.; Matsushima-Nishiwaki, R.; Kato, K.; Minamitani, C.; Otsuka, T.; Kozawa, O. Wnt3a regulates tumor necrosis factor-alpha-stimulated interleukin-6 release in osteoblasts. Mol. Cell. Endocrinol., 2011, 331(1), 66-72.
77. Takada, I.; Kouzmenko, A.P.; Kato, S. Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat. Rev. Rheumatol., 2009, 5, 442-447.
78. Takada, I.; Kouzmenko, A.P.; Kato, S. Molecular switching of osteoblastogenesis versus adipogenesis: implications for targeted therapies. Expert Opin. Ther. Targets, 2009, 13, 593-603.
79. Takada, I.; Suzawa, M.; Matsumoto, K.; Kato, S. Suppression of PPAR transactivation switches cell fate of bone marrow stem cells from adipocytes into osteoblasts. Ann. NY Acad. Sci., 2007, 1116, 182-195.
80. Liu, J. and Farmer, S.R. Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J. Biol. Chem., 2004, 279, 45020-45027.
81. Christodoulides, C.; Laudes, M.; Cawthorn, W.P.; Schinner, S.; Soos, M.; O'Rahilly, S.; Sethi, J.K.; Vidal-Puig, A. The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis. J. Cell Sci., 2006, 119, 2613-2620.
82. Bergenstock, M.K. and Partridge, N.C. Parathyroid hormone stimulation of noncanonical Wnt signaling in bone. Ann. NY Acad. Sci., 2007, 1116, 354-359.
83. Bodine, P.V.; Seestaller-Wehr, L.; Kharode, Y.P.; Bex, F.J.; Komm, B.S. Bone anabolic effects of parathyroid hormone are blunted by deletion of the Wnt antagonist secreted frizzled-related protein-1. J. Cell. Physiol., 2007, 210, 352-357.
84. Hayashi, K.; Yamaguchi, T.; Yano, S.; Kanazawa, I.; Yamauchi, M.; Yamamoto, M.; Sugimoto, T. BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: potential therapeutic targets for glucocorticoid-induced osteoporosis. Biochem. Biophys. Res. Commun., 2009, 379, 261-266.
85. Suzuki, A.; Ozono, K.; Kubota, T.; Kondou, H.; Tachikawa, K.; Michigami, T. PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. J. Cell. Biochem., 2008, 104, 304-317.
86. Iwaniec, U.T.; Wronski, T.J.; Liu, J.; Rivera, M.F.; Arzaga, R.R.; Hansen, G.; Brommage, R. PTH stimulates bone formation in mice deficient in Lrp5. J. Bone Miner. Res., 2007, 22, 394-402.
87. Kramer, I.; Keller, H.; Leupin, O.; Kneissel, M. Does osteocytic SOST suppression mediate PTH bone anabolism? Trends Endocrinol. Metab., 2010, 21, 237-244.
88. Drake, M.T.; Srinivasan, B.; Modder, U.I.; Peterson, J.M.; McCready, L.K.; Riggs, B.L.; Dwyer, D.; Stolina, M.; Kostenuik, P.; Khosla, S. Effects of Parathyroid Hormone Treatment on Circulating Sclerostin Levels in Postmenopausal Women. J. Clin. Endocrinol. Metab., 2010, 95, 5056-5062.
89. Zhang, L.; Su, P.; Xu, C.; Chen, C.; Liang, A.; Du, K.; Peng, Y.; Huang, D. Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARgamma expression and enhancing Runx2 expression. J. Pineal Res., 2010, 49(4), 364-372.
90. Liu, X.H.; Kirschenbaum, A.; Yao, S.; Levine, A.C. Androgens promote preosteoblast differentiation via activation of the canonical Wnt signaling pathway. Ann. N Y Acad. Sci., 2007, 1116, 423-431.
91. Hendy, G.N.; Hruska, K.A.; Mathew, S.; Goltzman, D. New insights into mineral and skeletal regulation by active forms of vitamin D. Kidney Int., 2006, 69, 218-223.
92. Li, Y.L. and Xiao, Z.S. Advances in Runx2 regulation and its isoforms. Med. Hypotheses, 2007, 68, 169-175.
93. Fretz, J.A.; Zella, L.A.; Kim, S.; Shevde, N.K.; Pike, J.W. 1,25-Dihydroxyvitamin D3 induces expression of the Wnt signaling coregulator LRP5 via regulatory elements located significantly downstream of the gene's transcriptional start site. J Steroid Biochem Mol Biol, 2007, 103, 440-445
94. Cianferotti, L.; Demay, M.B. VDR-mediated inhibition of DKK1 and SFRP2 suppresses adipogenic differentiation of murine bone marrow stromal cells. J. Cell. Biochem., 2007, 101, 80-88.
95. Palmer, H.G.; Gonzalez-Sancho, J.M.; Espada, J.; Berciano, M.T.; Puig, I.; Baulida, J.; Quintanilla, M.; Cano, A.; de Herreros, A.G.; Lafarga, M.; Munoz, A. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J. Cell Biol., 2001, 154, 369-387.
96. Shah, S.; Pishvaian, M.J.; Easwaran, V.; Brown, P.H.; Byers, S.W. The role of cadherin, beta-catenin, and AP-1 in retinoid-regulated carcinoma cell differentiation and proliferation. J. Biol. Chem., 2002, 277, 25313-25322.
97. Moore, W.J.; Kern, J.C.; Bhat, R.; Bodine, P.V.; Fukyama, S.; Krishnamurthy, G.; Magolda, R.L.; Pitts, K.; Stauffer, B.; Trybulski, E.J. Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides: part II. Bioorg. Med. Chem., 2010, 18, 190-201.
98. Moore, W.J.; Kern, J.C.; Bhat, R.; Commons, T.J.; Fukayama, S.; Goljer, I.; Krishnamurthy, G.; Magolda, R.L.; Nogle, L.; Pitts, K.; Stauffer, B.; Trybulski, E.J.; Welmaker, G.S.; Wilson, M.; Bodine, P.V. Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides. J. Med. Chem., 2009, 52, 105-116.
99. Bodine, P.V.; Stauffer, B.; Ponce-de-Leon, H.; Bhat, R.A.; Mangine, A.; Seestaller-Wehr, L.M.; Moran, R.A.; Billiard, J.; Fukayama, S.; Komm, B.S.; Pitts, K.; Krishnamurthy, G.; Gopalsamy, A.; Shi, M.; Kern, J.C.; Commons, T.J.; Woodworth, R.P.; Wilson, M.A.; Welmaker, G.S.; Trybulski, E.J.; Moore, W.J. A small molecule inhibitor of the Wnt antagonist secreted frizzledrelated protein-1 stimulates bone formation. Bone, 2009, 44, 1063-1068.
100. Wang, F.S.; Ko, J.Y.; Lin, C.L.; Wu, H.L.; Ke, H.J.; Tai, P.J. Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats. Bone, 2007, 40, 485-492.
101. Wang, F.S.; Ko, J.Y.; Yeh, D.W.; Ke, H.C.; Wu, H.L. Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation, and bone mass loss. Endocrinology, 2008, 149, 1793-1801.
102. Gregory, C.A.; Singh, H.; Perry, A.S.; Prockop, D.J. The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow. J. Biol. Chem., 2003, 278, 28067-28078.
103. Glantschnig, H.; Hampton, R.A.; Lu, P.; Zhao, J.Z.; Vitelli, S.; Huang, L.; Haytko, P.; Cusick, T.; Ireland, C.; Jarantow, S.W.; Ernst, R.; Wei, N.; Nantermet, P.; Scott, K.R.; Fisher, J.E.; Talamo, F.; Orsatti, L.; Reszka, A.A.; Sandhu, P.; Kimmel, D.; Flores, O.; Strohl, W.; An, Z.; Wang, F. Generation and selection of novel fully human monoclonal antibodies that neutralize Dickkopf-1 (DKK1) inhibitory function in vitro and increase bone mass in vivo. J. Biol. Chem., 2010, 285(51), 40135-40147.
104. Fulciniti, M.; Tassone, P.; Hideshima, T.; Vallet, S.; Nanjappa, P.; Ettenberg, S.A.; Shen, Z.; Patel, N.; Tai, Y.T.; Chauhan, D.; Mitsiades, C.; Prabhala, R.; Raje, N.; Anderson, K.C.; Stover, D.R.; Munshi, N.C. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 2009, 114, 371-379.
105. Heath, D.J.; Chantry, A.D.; Buckle, C.H.; Coulton, L.; Shaughnessy, J.D. Jr.; Evans, H.R.; Snowden, J.A.; Stover, D.R.; Vanderkerken, K.; Croucher, P.I. Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J. Bone Miner. Res., 2009, 24, 425-436.
106. Lyritis, G.P.; Georgoulas, T.; Zafeiris, C.P. Bone anabolic versus bone anticatabolic treatment of postmenopausal osteoporosis. Ann. NY Acad. Sci., 2010, 1205, 277-283.
107. Roux, S. New treatment targets in osteoporosis. Joint Bone Spine, 2010, 77, 222-228.