Experimental Hematology
Volume 38, Issue 2 , Pages 141-153 , February 2010

Distinct transcriptional profiles characterize bone microenvironment mesenchymal cells rather than osteoblasts in relationship with multiple myeloma bone disease

  • Katia Todoerti

      Affiliations

    • Dipartimento di Scienze Mediche, Università di Milano e U.O. Ematologia 1, Fondazione IRCCS Policlinico, Milan, Italy
  • ,
  • Gina Lisignoli

      Affiliations

    • Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli, Bologna, Italy
  • ,
  • Paola Storti

      Affiliations

    • Ematologia e Centro Trapianti Midollo Osseo, Dipartimento di Medicina Interna e Scienze Biomediche, Azienda Ospedaliero-Universitaria, Parma, Italy
  • ,
  • Luca Agnelli

      Affiliations

    • Dipartimento di Scienze Mediche, Università di Milano e U.O. Ematologia 1, Fondazione IRCCS Policlinico, Milan, Italy
  • ,
  • Francesca Novara

      Affiliations

    • Dipartimento di Patologia Umana ed Ereditaria, Sezione Biologia generale e Genetica Medica, University of Pavia, Pavia, Italy
  • ,
  • Cristina Manferdini

      Affiliations

    • Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli, Bologna, Italy
  • ,
  • Katia Codeluppi

      Affiliations

    • Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli, Bologna, Italy
  • ,
  • Simona Colla

      Affiliations

    • Ematologia e Centro Trapianti Midollo Osseo, Dipartimento di Medicina Interna e Scienze Biomediche, Azienda Ospedaliero-Universitaria, Parma, Italy
  • ,
  • Monica Crugnola

      Affiliations

    • Ematologia e Centro Trapianti Midollo Osseo, Dipartimento di Medicina Interna e Scienze Biomediche, Azienda Ospedaliero-Universitaria, Parma, Italy
  • ,
  • Manuela Abeltino

      Affiliations

    • Ematologia e Centro Trapianti Midollo Osseo, Dipartimento di Medicina Interna e Scienze Biomediche, Azienda Ospedaliero-Universitaria, Parma, Italy
  • ,
  • Marina Bolzoni

      Affiliations

    • Ematologia e Centro Trapianti Midollo Osseo, Dipartimento di Medicina Interna e Scienze Biomediche, Azienda Ospedaliero-Universitaria, Parma, Italy
  • ,
  • Valentina Sgobba

      Affiliations

    • Ematologia e Centro Trapianti Midollo Osseo, Dipartimento di Medicina Interna e Scienze Biomediche, Azienda Ospedaliero-Universitaria, Parma, Italy
  • ,
  • Andrea Facchini

      Affiliations

    • Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli, Bologna, Italy
  • ,
  • Giorgio Lambertenghi-Deliliers

      Affiliations

    • Dipartimento di Scienze Mediche, Università di Milano e U.O. Ematologia 1, Fondazione IRCCS Policlinico, Milan, Italy
  • ,
  • Orsetta Zuffardi

      Affiliations

    • Dipartimento di Patologia Umana ed Ereditaria, Sezione Biologia generale e Genetica Medica, University of Pavia, Pavia, Italy
  • ,
  • Vittorio Rizzoli

      Affiliations

    • Ematologia e Centro Trapianti Midollo Osseo, Dipartimento di Medicina Interna e Scienze Biomediche, Azienda Ospedaliero-Universitaria, Parma, Italy
  • ,
  • Antonino Neri

      Affiliations

    • Dipartimento di Scienze Mediche, Università di Milano e U.O. Ematologia 1, Fondazione IRCCS Policlinico, Milan, Italy
  • ,
  • Nicola Giuliani

      Affiliations

    • Ematologia e Centro Trapianti Midollo Osseo, Dipartimento di Medicina Interna e Scienze Biomediche, Azienda Ospedaliero-Universitaria, Parma, Italy
    • Corresponding Author InformationOffprint requests to: Nicola Giuliani, M.D., Ph.D., Department of Internal Medicine and Biomedical Science, University of Parma, Via Gramsci 14, Parma 43100, Italy

Received 18 August 2009 ,Revised 5 November 2009 ,Accepted 24 November 2009.

References 

  1. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860–1873
  2. Lentzsch S, Ehrlich LA, Roodman GD. Pathophysiology of multiple myeloma bone disease. Hematol Oncol Clin North Am. 2007;21:1035–1049
  3. Bataille R, Chappard D, Marcelli C, et al. Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease. J Clin Oncol. 1989;7:1909–1914
  4. Giuliani N, Rizzoli V, Roodman GD. Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood. 2006;108:3992–3996
  5. 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
  6. Yaccoby S, Wezeman MJ, Zangari M, et al. Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model. Haematologica. 2006;91:192–199
  7. Robbiani DF, Chesi M, Bergsagel PL. Bone lesions in molecular subtypes of multiple myeloma. N Engl J Med. 2004;351:197–198
  8. 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
  9. Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood. 2007;109:2106–2111
  10. Corre J, Mahtouk K, Attal M, et al. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia. 2007;21:1079–1088
  11. Garderet L, Mazurier C, Chapel A, et al. Mesenchymal stem cell abnormalities in patients with multiple myeloma. Leuk Lymphoma. 2007;48:2032–2041
  12. 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
  13. Robey PG, Termine JD. Human bone cells in vitro. Calcif Tissue Int. 1985;37:453–460
  14. Lisignoli G, Piacentini A, Toneguzzi S, et al. Osteoblasts and stromal cells isolated from femora in rheumatoid arthritis (RA) and osteoarthritis (OA) patients express IL-11, leukaemia inhibitory factor and oncostatin M. Clin Exp Immunol. 2000;119:346–353
  15. Giuliani N, Lisignoli G, Colla S, et al. CC-chemokine ligand 20/macrophage inflammatory protein-3alpha and CC-chemokine receptor 6 are overexpressed in myeloma microenvironment related to osteolytic bone lesions. Cancer Res. 2008;68:6840–6850
  16. Mattioli M, Agnelli L, Fabris S, et al. Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma. Oncogene. 2005;24:2461–2473
  17. Agnelli L, Bicciato S, Mattioli M, et al. Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations. J Clin Oncol. 2005;23:7296–7306
  18. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98:5116–5121
  19. Schadt EE, Li C, Su C, Wong WH. Analyzing high-density oligonucleotide gene expression array data. J Cell Biochem. 2000;80:192–202
  20. Giuliani N, Colla S, Morandi F, Barille-Nion S, Rizzoli V. Lack of receptor activator of nuclear factor-kB ligand (RANKL) expression and functional production by human multiple myeloma cells. Haematologica. 2005;90:275–278
  21. Haaber J, Abildgaard N, Knudsen LM, et al. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis. Br J Haematol. 2008;140:25–35
  22. Magrangeas F, Nasser V, Avet-Loiseau H, et al. Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. Blood. 2003;101:4998–5006
  23. Edwards CM, Zhuang J, Mundy GR. The pathogenesis of the bone disease of multiple myeloma. Bone. 2008;42:1007–1013
  24. Mitsiades CS, McMillin DW, Klippel S, et al. The role of the bone marrow microenvironment in the pathophysiology of myeloma and its significance in the development of more effective therapies. Hematol Oncol Clin North Am. 2007;21:1007–1034
  25. Giuliani N, Rizzoli V. Myeloma cells and bone marrow osteoblast interactions: role in the development of osteolytic lesions in multiple myeloma. Leuk Lymphoma. 2007;48:2323–2329
  26. Roodman GD. Mechanisms of bone lesions in multiple myeloma and lymphoma. Cancer. 1997;80(Suppl):1557–1563
  27. Wallace SR, Oken MM, Lunetta KL, Panoskaltsis-Mortari A, Masellis AM. Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients. Cancer. 2001;91:1219–1230
  28. Garayoa M, Garcia JL, Santamaria C, et al. Mesenchymal stem cells from multiple myeloma patients display distinct genomic profile as compared with those from normal donors. Leukemia. 2009;23:1515–1527
  29. Tanabe S, Sato Y, Suzuki T, Suzuki K, Nagao T, Yamaguchi T. Gene expression profiling of human mesenchymal stem cells for identification of novel markers in early- and late-stage cell culture. J Biochem. 2008;144:399–408
  30. Schilling T, Küffner R, Klein-Hitpass L, Zimmer R, Jakob F, Schütze N. Microarray analyses of transdifferentiated mesenchymal stem cells. J Cell Biochem. 2008;103:413–433
  31. Sakaguchi Y, Sekiya I, Yagishita K, Ichinose S, Shinomiya K, Muneta T. Suspended cells from trabecular bone by collagenase digestion become virtually identical to mesenchymal stem cells obtained from marrow aspirates. Blood. 2004;104:2728–2735
  32. Sanchez-Guijo FM, Blanco JF, Cruz G, et al. Multiparametric comparison of mesenchymal stromal cells obtained from trabecular bone by using a novel isolation method with those obtained by iliac crest aspiration from the same subjects. Cell Tissue Res. 2009;336:501–507
  33. Lisignoli G, Codeluppi K, Todoerti K, et al. Gene array profile identifies collagen type XV as a novel human osteoblast-secreted matrix protein. J Cell Physiol. 2009;220:401–409
  34. Lisignoli G, Cristino S, Toneguzzi S, et al. IL1beta and TNFalpha differently modulate CXCL13 chemokine in stromal cells and osteoblasts isolated from osteoarthritis patients: evidence of changes associated to cell maturation. Exp Gerontol. 2004;39:659–665
  35. Jilka RL, Weinstein RS, Parfitt AM, Manolagas SC. Quantifying osteoblast and osteocyte apoptosis: challenges and rewards. J Bone Miner Res. 2007;22:1492–1501
  36. Gruber HE, Ivey JL, Thompson ER, Chesnut CH, Baylink DJ. Osteoblast and osteoclast cell number and cell activity in postmenopausal osteoporosis. Miner Electrolyte Metab. 1986;12:246–254
  37. Bataille R, Chappard D, Marcelli C, et al. Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma. J Clin Invest. 1991;88:62–66
  38. Phinney DG, Gray AJ, Hill K, Pandey A. Murine mesenchymal and embryonic stem cells express a similar Hox gene profile. Biochem Biophys Res Commun. 2005;338:1759–1765
  39. Chung N, Jee BK, Chae SW, Jeon YW, Lee KH, Rha HK. HOX gene analysis of endothelial cell differentiation in human bone marrow-derived mesenchymal stem cells. Mol Biol Rep. 2009;36:227–235
  40. Ria R, Piccoli C, Cirulli T, et al. Endothelial differentiation of hematopoietic stem and progenitor cells from patients with multiple myeloma. Clin Cancer Res. 2008;14:1678–1685
  41. Vacca A, Ria R, Semeraro F, et al. Endothelial cells in the bone marrow of patients with multiple myeloma. Blood. 2003;102:3340–3348
  42. Serria MS, Ikeda H, Omoteyama K, Hirokawa J, Nishi S, Sakai M. Regulation and differential expression of the c-maf gene in differentiating cultured cells. Biochem Biophys Res Commun. 2003;310:318–326
  43. MacLean HE, Kim JI, Glimcher MJ, Wang J, Kronenberg HM, Glimcher LH. Absence of transcription factor c-maf causes abnormal terminal differentiation of hypertrophic chondrocytes during endochondral bone development. Dev Biol. 2003;262:51–63
  44. Giuliani N, Bataille R, Mancini C, Lazzaretti M, Barillé S. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood. 2001;98:3527–3533
  45. Aqeilan RI, Hassan MQ, de Bruin A, et al. The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism. J Biol Chem. 2008;283:21629–21639
  46. Li X, Pennisi A, Yaccoby S. Role of decorin in the antimyeloma effects of osteoblasts. Blood. 2008;112:159–168
  47. Atkins GJ, Kostakis P, Pan B, et al. RANKL expression is related to the differentiation state of human osteoblasts. J Bone Miner Res. 2003;18:1088–1098
  48. Qiang YW, Shaughnessy JD, Yaccoby S. Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth. Blood. 2008;112:374–382
  49. Edwards CM, Edwards JR, Lwin ST, et al. 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
  50. 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
  51. 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
  52. Suh JH, Lee HW, Lee JW, Kim JB. Hes1 stimulates transcriptional activity of Runx2 by increasing protein stabilization during osteoblast differentiation. Biochem Biophys Res Commun. 2008;367:97–102
  53. Li X, Huang M, Zheng H, et al. CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation. J Cell Biol. 2008;181:959–972

PII: S0301-472X(09)00453-6

doi: 10.1016/j.exphem.2009.11.009

Experimental Hematology
Volume 38, Issue 2 , Pages 141-153 , February 2010