Experimental Hematology
Volume 37, Issue 8 , Pages 879-886 , August 2009

Osteogenic differentiation of mesenchymal stem cells in multiple myeloma: Identification of potential therapeutic targets

Received 16 March 2009 ,Revised 10 April 2009 ,Accepted 20 April 2009.

References 

  1. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860–1873
  2. Giuliani N, Rizzoli V. GD Roodman. Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood. 2006;108:3992–3996
  3. Vejlgaard T, Abildgaard N, Jans H, et al. Abnormal bone turnover in monoclonal gammaopathy of undetermined significance: analyses of type I collagen telopeptide, osteocalcin, bone-specific alkaline phosphatase and propeptides of type I and type III. procollagens. Eur J Haematol. 1997;58:104–108
  4. Hjorth-Hansen H, Seifert MF, Borset M, et al. Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. J Bone Miner Res. 1999;14:256–263
  5. Franceschi RT, Ge C, Xiao G, et al. Transcriptional regulation of osteoblasts. Ann N Y Acad Sci. 2007;1116:196–207
  6. Deng ZL, Sharff KA, Tang N, et al. Regulation of osteogenic differentiation during skeletal development. Front Biosci. 2008;13:2001–2021
  7. Ducy P, Zhang R, Geoffroy V, et al. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. 1997;89:747–754
  8. Franceschi RT, Xiao G. Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J Cell Biochem. 2003;88:446–454
  9. Liu W, Toyosawa S, Furuichi T, et al. Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J Cell Biol. 2001;155:157–166
  10. Geoffroy V, Kneissel M, Fournier B, et al. High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage. Mol Cell Biol. 2002;22:6222–6233
  11. Shui C, Spelsberg TC, Riggs BL, Khosla S. Changes in Runx2/Cbfa1 expression and activity during osteoblastic differentiation of human bone marrow stromal cells. J Bone Miner Res. 2003;18:213–221
  12. Gronthos S, Zannettino AC, Hay SJ, et al. Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. J Cell Sci. 2003;116:1827–1835
  13. Xiao G, Jiang D, Thomas P, et al. MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor. Cbfa1. J Biol Chem. 2000;275:4453–4459
  14. Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in osteoblasts and bone diseases. Gene. 2004;341:19–39
  15. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. 2006;116:1202–1209
  16. Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006;281:22429–22433
  17. Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A. 2005;102:3324–3329
  18. Rawadi G, Vayssiere B, Dunn F, et al. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res. 2003;18:1842–1853
  19. Niida A, Hiroko T, Kasai M, et al. DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene. 2004;23:8520–8526
  20. Galli LM, Barnes T, Cheng T, et al. Differential inhibition of Wnt-3a by Sfrp-1, Sfrp-2, and Sfrp-3. Dev Dyn. 2006;235:681–690
  21. Li J, Sarosi I, Cattley RC, et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone. 2006;39:754–766
  22. Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci. 2003;116:2627–2634
  23. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346:1513–1521
  24. Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–523
  25. Ai M, Holmen SL, Van Hul W, et al. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol. 2005;25:4946–4955
  26. Kato M, Patel MS, Levasseur R, et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol. 2002;157:303–314
  27. Gaur T, Lengner CJ, Hovhannisyan H, et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem. 2005;280:33132–33140
  28. Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A. 2005;102:3324–3329
  29. de Boer J, Siddappa R, Gaspar C, et al. Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells. Bone. 2004;34:818–826
  30. Boland GM, Perkins G, Hall DJ, et al. Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem. 2004;93:1210–1230
  31. Baksh D, Boland GM, Tuan RS. Cross-talk between Wnt signaling pathways in human mesenchymal stem cells leads to functional antagonism during osteogenic differentiation. J Cell Biochem. 2007;101:1109–1124
  32. Baksh D, Tuan RS. 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
  33. Li X, Liu P, Liu W, et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet. 2005;37:945–952
  34. van der Horst G, van der Werf SM, Farih-Sips H, et al. Downregulation of Wnt signaling by increased expression of Dickkopf-1 and -2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells. J Bone Miner Res. 2005;20:1867–1877
  35. Vaes BL, Dechering KJ, van Someren EP, et al. Microarray analysis reveals expression regulation of Wnt antagonists in differentiating osteoblasts. Bone. 2005;36:803–811
  36. Ling L, Nurcombe V, Cool SM. Wnt signaling controls the fate of mesenchymal stem cells. Gene. 2009;433:1–7
  37. Katoh M, Katoh M. WNT signaling pathway and stem cell signaling network. Clin Cancer Res. 2007;13:4042–4045
  38. Chang J, Sonoyama W, Wang Z, et al. 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
  39. Liu Y, Rubin B, Bodine PV, et al. Wnt5a induces homodimerization and activation of Ror2 receptor tyrosine kinase. J Cell Biochem. 2008;105:497–502
  40. Liu Y, Ross JF, Bodine PV, et al. Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation. Mol Endocrinol. 2007;21:3050–3061
  41. Liu Y, Bhat RA, Seestaller-Wehr LM, et al. The orphan receptor tyrosine kinase Ror2 promotes osteoblast differentiation and enhances ex vivo bone formation. Mol Endocrinol. 2007;21:376–387
  42. Billiard J, Way DS, Seestaller-Wehr LM, et al. The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells. Mol Endocrinol. 2005;19:90–101
  43. Takada I, Mihara M, Suzawa M, et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol. 2007;9:1273–1285
  44. Giuliani N, Colla S, Morandi F, et al. myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. Blood. 2005;106:2472–2483
  45. Corre J, Mahtouk K, Attal M, et al. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia. 2007;21:1079–1088
  46. Garderet L, Mazurier C, Chapel A, et al. Mesenchymal stem cell abnormalities in patients with multiple myeloma. Leuk Lymphoma. 2007;48:2032–2041
  47. Arnulf B, Lecourt S, Soulier J, et al. Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma. Leukemia. 2007;21:158–163
  48. Mori Y, Shimizu N, Dallas M, et al. Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood. 2004;104:2149–2154
  49. Ely SA, Knowles DM. Expression of CD56/neural cell adhesion molecule correlates with the presence of lytic bone lesions in multiple myeloma and distinguishes myeloma from monoclonal gamyelomaopathy of undetermined significance and lymphomas with plasmacytoid differentiation. Am J Pathol. 2002;160:1293–1299
  50. Weitzmann MN, Roggia C, Toraldo G, et al. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest. 2002;110:1643–1650
  51. Giuliani N, Colla S, Sala R, et al. Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Blood. 2002;100:4615–4621
  52. Standal T, Abildgaard N, Fagerli UM, et al. HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood. 2007;109:3024–3030
  53. Hong JH, Hwang ES, McManus MT, et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science. 2005;309:1074–1078
  54. Li B, Shi M, Li J, et al. Elevated tumor necrosis factor-alpha suppresses TAZ expression and impairs osteogenic potential of Flk-1+ mesenchymal stem cells in patients with multiple myeloma. Stem Cells Dev. 2007;16:921–930
  55. Krishnan V, Moore TL, Ma YL, et al. Parathyroid hormone bone anabolic action requires Cbfa1/Runx2-dependent signaling. Mol Endocrinol. 2003;17:423–435
  56. Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone. 2007;40:1434–1446
  57. Zhao Z, Zhao M, Xiao G, et al. Gene transfer of the Runx2 transcription factor enhances osteogenic activity of bone marrow stromal cells in vitro and in vivo. Mol Ther. 2005;12:247–253
  58. Ehrlich LA, Chung HY, Ghobrial I, et al. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood. 2005;106:1407–1414
  59. Lee JW, Chung HY, Ehrlich LA, et al. IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood. 2004;103:2308–2315
  60. Giuliani N, Morandi F, Tagliaferri S, et al. Interleukin-3 (IL-3) is overexpressed by T lymphocytes in multiple myeloma patients. Blood. 2006;107:841–842
  61. Tian E, Zhan F, Walker R, et al. 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
  62. Giuliani N, Morandi F, Tagliaferri S, et al. Production of wnt inhibitors by myeloma cells: potential effects on canonical wnt pathway in the bone microenvironment. Cancer Res. 2007;67:7665–7674
  63. Oshima T, Abe M, Asano J, et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood. 2005;106:3160–3165
  64. De Toni F, Racaud-Sultan C, Chicanne G, et al. A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia. Oncogene. 2006;25:3113–3122
  65. Gunn WG, Conley A, Deininger L, et al. 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
  66. Qiang YW, Chen Y, Stephens O, et al. 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
  67. Yaccoby S, Ling W, Zhan F, et al. Antibody-based inhibition of DKK1 suppresses tumor- induced bone resorption and multiple myeloma growth in- vivo. Blood. 2007;109:2106–2111
  68. Qiang YW, Shaughnessy JD, Yaccoby S. Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth. Blood. 2008;112:374–382
  69. Edwards CM, Edwards JR, Lwin ST, et al. Mundy GR. 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
  70. Garrett IR, Chen D, Gutierrez G, et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest. 2003;111:1771–1782
  71. Zhao M, Qiao M, Oyajobi BO, et al. E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem. 2003;278:27939–27944
  72. Zangari M, Esseltine D, Lee CK, et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol. 2005;131:71–73
  73. Zangari M, Yaccoby S, Cavallo F, et al. Response to bortezomib and activation of osteoblasts in multiple myeloma. Clin Lymphoma Myeloma. 2006;7:109–114
  74. Shimazaki C, Uchida R, Nakano S, et al. High serum bone-specific alkaline phosphatase level after bortezomib-combined therapy in refractory multiple myeloma: possible role of bortezomib on osteoblast differentiation. Leukemia. 2005;19:1102–1103
  75. Heider U, Kaiser M, Muller C, et al. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur J Haematol. 2006;77:233–238
  76. Terpos E, Heath DJ, Rahemtulla A, et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodeling in patients with relapsed multiple myeloma. Br J Haematol. 2006;135:688–692
  77. Giuliani N, Morandi F, Tagliaferri S, et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood. 2007;110:334–338
  78. Mukherjee S, Raje N, Schoonmaker JA, et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest. 2008;118:491–504
  79. Qiang YW, Hu B, Chen Y, et al. Bortezomib induces osteoblast differentiation via Wnt-independent activation of {beta}-catenin/TCF signaling. Blood. 2009;113:4319–4330
  80. Girotra M, Rubin MR, Bilezikian JP. The use of parathyroid hormone in the treatment of osteoporosis. Rev Endocr Metab Disord. 2006;7:113–121
  81. Bellido T, Ali AA, Plotkin LI, et al. Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem. 2003;278:50259–50272
  82. Kousteni S, Bilezikian JP. The cell biology of parathyroid hormone in osteoblasts. Curr Osteoporos Rep. 2008;6:72–76
  83. Weber JM, Forsythe SR, Christianson CA, et al. Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells. Bone. 2006;39:485–493
  84. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–846
  85. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425:836–841
  86. Garrett RW, Emerson SG. The role of parathyroid hormone and insulin-like growth factors in hematopoietic niches: physiology and pharmacology. Mol Cell Endocrinol. 2008;288:6–10
  87. Pennisi A, Ling W, Perkins P, et al. PTH and bortezomib suppress growth of primary human myeloma through increased bone formation in vivo. [abstract] Blood. 2006;108:Abstract 509
  88. Zangari M, Pappas L, Zhan F, et al. Parathyroid hormones (PTH) serum variations are associated with bortezomib response in multiple myeloma patients. [abstract] Blood. 2008;112:Abstract 2783

PII: S0301-472X(09)00134-9

doi: 10.1016/j.exphem.2009.04.004

Experimental Hematology
Volume 37, Issue 8 , Pages 879-886 , August 2009