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Expression of receptor activator of NF-κB ligand (RANKL) mRNA in human multiple myeloma cells

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Abstract

Purpose

Increased bone resorption is a hallmark of multiple myeloma and a result of excessive osteoclast activation. Recently, the receptor activator of NF-κB ligand (RANKL) was found to be the critical factor for osteoclastogenesis. Studies showed that myeloma cells induce RANKL expression in bone marrow stromal cells, but it remained a controversy whether myeloma cells directly express RANKL.

Methods

Therefore, we analyzed the expression of RANKL mRNA in freshly isolated CD138 positive plasma cells from patients with multiple myeloma and osteolytic bone lesions, using three different primer pairs against human RANKL.

Results

RANKL mRNA could be detected in bone marrow plasma cells from myeloma patients with osteolytic myeloma bone disease.

Conclusions

These findings show that myeloma cells directly express RANKL and indicate that specific blockade of RANKL may be an effective treatment for myeloma bone disease.

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Fig. 1A, B
Fig. 2A–D

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References

  1. Altamirano CV, Ma HJ, Parker KM, Glowalla A, Mikail AE, Sjak-Shie N, Vescio R, Berenson JR (2000) RANKL is expressed in multiple myeloma cell lines. Blood 96:365

    CAS  PubMed  Google Scholar 

  2. Atkins GJ, Haynes DR, Geary SM, Loric M, Crotti TN, Findlay DM (2000) Coordinated cytokine expression by stromal and hematopoietic cells during human osteoclast formation. Bone 26:653–661

    CAS  PubMed  Google Scholar 

  3. Ballester OF, Moscinski LC, Lyman GH, Chaney JV, Saba HI, Spiers AS, Klein C (1994) High levels of interleukin-6 are associated with low tumor burden and low growth fraction in multiple myeloma. Blood 83:1903–1908

    CAS  PubMed  Google Scholar 

  4. Bekker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT, Dunstan CR (2001) The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 16:348–360

    CAS  PubMed  Google Scholar 

  5. Body JJ, Greipp P, Coleman RE, Facon T, Geurs F, Fermand JP, Harousseau JL, Lipton A, Mariette X, Williams CD, Nakanishi A, Holloway D, Martin SW, Dunstan CR, Bekker PJ (2003) A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 97[Suppl 3]:887–892

  6. Callander NS, Roodman GD (2001) Myeloma bone disease. Semin Hematol 38:276–285

    CAS  PubMed  Google Scholar 

  7. Choi SJ, Cruz JC, Craig F, Chung H, Devlin RD, Roodman GD, Alsina M (2000) Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 96:671–675

    CAS  PubMed  Google Scholar 

  8. Croucher PI, Shipman CM, Lippitt J, Perry M, Asosingh K, Hijzen A, Brabbs AC, van Beek EJ, Holen I, Skerry TM, Dunstan CR, Russell GR, Van Camp B, Vanderkerken K (2001) Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 98:3534–3540

    Article  CAS  PubMed  Google Scholar 

  9. Eucker J, Eikel D, Heider U, Jakob C, Zavrski I, Gatz F, Mergenthaler HG, Jungclas H, Possinger K, Sezer O (2003) Liposomal daunorubicin (DaunoXome) in multiple myeloma: a modified VAD regimen using short-term infusion. Anticancer Drug 14:793–799

    Article  CAS  Google Scholar 

  10. Farrugia AN, Atkins GJ, To LB, Pan B, Horvath N, Kostakis P, Findlay DM, Bardy P, Zannettino AC (2003) Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 63:5438–5445

    CAS  PubMed  Google Scholar 

  11. Giuliani N, Bataille R, Mancini C, Lazzaretti M, Barille S (2001) Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood 98:3527–3533

    Article  CAS  PubMed  Google Scholar 

  12. Heider U, Langelotz C, Jakob C, Zavrski I, Fleissner C, Eucker J, Possinger K, Hofbauer LC, Sezer O (2003) Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin Cancer Res 9:1436–1440

    CAS  PubMed  Google Scholar 

  13. Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, Khosla S (1999) Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140:4382–4389

    CAS  PubMed  Google Scholar 

  14. Hofbauer LC, Neubauer A, Heufelder AE (2001a) Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer 92:460–470

    Article  CAS  PubMed  Google Scholar 

  15. Hofbauer LC, Shui C, Riggs BL, Dunstan CR, Spelsberg TC, O’Brien T, Khosla S (2001b) Effects of immunosuppressants on receptor activator of kappaB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Commun 280:334–339

    Article  CAS  PubMed  Google Scholar 

  16. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, Wang L, Xia XZ, Elliott R, Chiu L, Black T, Scully S, Capparelli C, Morony S, Shimamoto G, Bass MB, Boyle WJ (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96:3540–3545

    CAS  PubMed  Google Scholar 

  17. Ikeda T, Kasai M, Utsuyama M, Hirokawa K (2001) Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. Endocrinology 142:1419–1426

    Article  CAS  PubMed  Google Scholar 

  18. Khosla S (2001) Minireview: the OPG/RANKL/RANK system. Endocrinology 142:5050–5055

    CAS  PubMed  Google Scholar 

  19. Kinpara K, Mogi M, Kuzushima M, Togari A (2000) Osteoclast differentiation factor in human osteosarcoma cell line. J Immunoassay 21:327–340

    CAS  PubMed  Google Scholar 

  20. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176

    PubMed  Google Scholar 

  21. Lacy MQ, Donovan KA, Heimbach JK, Ahmann GJ, Lust JA (1999) Comparison of interleukin-1 beta expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma. Blood 93:300–305

    CAS  PubMed  Google Scholar 

  22. Mitsiades CS, Mitsiades N, Poulaki V, Hayashi T, Hideshima T, Podar K, LeBlanc R, Catley L, Tai Y, Chauhan D, Lin B, Schlossman R, Richardson PG, Munshi N, Treon SP, Anderson KC (2001) Receptor activator of nuclear factor-kB (RANK) ligand expression in human multiple myeloma cells. Blood 98[Suppl 1]:638

  23. Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, Sakai H (2000) Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-kappaB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun 275:768–775

    Article  CAS  PubMed  Google Scholar 

  24. Niemöller K, Jakob C, Heider U, Zavrski I, Eucker J, Kaufmann O, Possinger K, Sezer O (2003) Bone marrow angiogenesis and its correlation with other disease characteristics in multiple myeloma in stage I versus stage II-III. J Cancer Res Clin Oncol 129:234–238

    PubMed  Google Scholar 

  25. Oyajobi BO, Traianedes K, Yoneda T, Mundy GR (1998) Expression of Rank ligand (RankL) by myeloma cells requires binding to bone marrow stromal cells via an a4b1-VCAM-1 interaction. Bone 23:S180

    Google Scholar 

  26. Oyajobi BO, Garrett IR, Williams PJ, Yoneda T, Anderson DM, Mundy GR (2000) A soluble murine receptor activator of NF-kB-hman immunoglobulin fusion protein (RANK.Fc) inhibits bone resorption in a murine model of human multiple myeloma bone disease. J Bone Miner Res 15[Suppl 1]:1151

  27. Pearse RN, Sordillo EM, Yaccoby S, Wong BR, Liau DF, Colman N, Michaeli J, Epstein J, Choi Y (2001) Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci USA 98:11581–11586

    Article  CAS  PubMed  Google Scholar 

  28. Plesner T, Boissy P, Dartell M, Norrild K, Hastrup N, Rasmussen M, Gaarsdal E, Delaissé JM, Anderson D (2001) Myeloma cells express and release Rank-ligand that promotes the generation of osteoclast-like cells. VIIIth International Myeloma Workshop, p 204

  29. Roodman GD (2001) Biology of osteoclast activation in cancer. J Clin Oncol 19:3562–3571

    CAS  PubMed  Google Scholar 

  30. Roux S, Meignin V, Quillard J, Meduri G, Guiochon-Mantel A, Fermand JP, Milgrom E, Mariette X (2002) RANK (receptor activator of nuclear factor-kappaB) and RANKL expression in multiple myeloma. Br J Haematol 117:86–92

    Article  CAS  PubMed  Google Scholar 

  31. Sati HI, Greaves M, Apperley JF, Russell RG, Croucher PI (1999) Expression of interleukin-1beta and tumour necrosis factor-alpha in plasma cells from patients with multiple myeloma. Br J Haematol 104:350–357

    Article  CAS  PubMed  Google Scholar 

  32. Sezer O, Heider U, Jakob C, Eucker J, Possinger K (2002a) Human bone marrow myeloma cells express RANKL. J Clin Oncol 20:353–354

    Google Scholar 

  33. Sezer O, Heider U, Jakob C, Zavrski I, Eucker J, Possinger K, Sers C, Krenn V (2002b) Immunocytochemistry reveals RANKL expression of myeloma cells. Blood 99:4646–4647

    Article  CAS  PubMed  Google Scholar 

  34. Sezer O, Heider U, Zavrski I, Kuhne CA, Hofbauer LC (2003) RANK ligand and osteoprotegerin in myeloma bone disease. Blood 101:2094–2098

    Article  CAS  PubMed  Google Scholar 

  35. Shi SR, Tandon AK, Haussmann RR, Kalra KL, Taylor CR (1993) Immunohistochemical study of intermediate filament proteins on routinely processed, celloidin-embedded human temporal bone sections by using a new technique for antigen retrieval. Acta Otolaryngol 113:48–54

    CAS  PubMed  Google Scholar 

  36. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander A, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319

    PubMed  Google Scholar 

  37. Standal T, Seidel C, Hjertner O, Plesner T, Sanderson RD, Waage A, Borset M, Sundan A (2002) Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 100:3002–3007

    Article  CAS  PubMed  Google Scholar 

  38. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ (1999) Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 20:345–357

    PubMed  Google Scholar 

  39. Terpos E, Politou M, Rahemtulla (2003) New insights into the pathophysiology and management of bone disease in multiple myeloma. Br J Haematol 123:758–769

    Article  CAS  PubMed  Google Scholar 

  40. Viereck V, Emons G, Lauck V, Frosch KH, Blaschke S, Grundker C, Hofbauer LC (2002) Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun 291:680–686

    Article  CAS  PubMed  Google Scholar 

  41. Westin JS, Ljunghall S, Nilsson K, Ljunggren O (1999) Human multiple myeloma cell lines express mRNA for osteoclast differentiation factor. J Bone Miner Res 14[Suppl 1]:S225

  42. Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J (2002) Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol 116:278–290

    Article  PubMed  Google Scholar 

  43. Zavrski I, Naujokat C, Niemöller K, Jakob C, Heider U, Langelotz C, Fleissner C, Eucker J, Possinger K, Sezer O (2003) Proteasome inhibitors induce growth inhibition and apoptosis in myeloma cell lines and in human bone marrow myeloma cells irrespective of chromosome 13 deletion. J Cancer Res Clin Oncol 129:383–391

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology and Oncology, Universitätsklinikum Charité, Humboldt-Universität Berlin, 10098 , Berlin, Germany

    Ulrike Heider, Ivana Zavrski, Christian Jakob, Katharina Bängeroth, Claudia Fleissner, Corinna Langelotz, Kurt Possinger & Orhan Sezer

  2. Division of Gastroenterology, Endocrinology and Metabolism, Philipps-Universität, Marburg, Germany

    Lorenz C. Hofbauer

  3. Department of Obstetrics and Gynecology, Georg-August-Universität Göttingen, Göttingen, Germany

    Volker Viereck

Authors
  1. Ulrike Heider
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  2. Ivana Zavrski
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  3. Christian Jakob
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  4. Katharina Bängeroth
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  6. Corinna Langelotz
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  7. Kurt Possinger
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  8. Lorenz C. Hofbauer
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Correspondence to Orhan Sezer.

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Heider, U., Zavrski, I., Jakob, C. et al. Expression of receptor activator of NF-κB ligand (RANKL) mRNA in human multiple myeloma cells. J Cancer Res Clin Oncol 130, 469–474 (2004). https://doi.org/10.1007/s00432-004-0578-3

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  • DOI: https://doi.org/10.1007/s00432-004-0578-3

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