Abstract
Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell–bone marrow interaction.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T et al. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 2004; 104: 2484–2491.
Abe M, Hiura K, Wilde J, Moriyama K, Hashimoto T, Ozaki S et al. Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma. Blood 2002; 100: 2195–2202.
Roodman GD . Pathogenesis of myeloma bone disease. Leukemia 2009; 23: 435–441.
Hiasa M, Abe M, Nakano A, Oda A, Amou H, Kido S et al. GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-alpha converting enzyme (TACE). Blood 2009; 114: 4517–4526.
Podar K, Chauhan D, Anderson KC . Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 2009; 23: 10–24.
Palumbo A, Anderson K . Multiple myeloma. N Engl J Med 2011; 364: 1046–1060.
Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC . Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007; 7: 585–598.
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: 2516–2520.
Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood 2012; 119: 4608–4613.
Edwards CM, Edwards JR, Lwin ST, Esparza J, Oyajobi BO, McCluskey B 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.
Asano J, Nakano A, Oda A, Amou H, Hiasa M, Takeuchi K et al. The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells. Leukemia 2011; 25: 1182–1188.
Oshima T, Abe M, Asano J, Hara T, Kitazoe K, Sekimoto E et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 2005; 106: 3160–3165.
Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B 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.
Fowler JA, Mundy GR, Lwin ST, Edwards CM . Bone marrow stromal cells create a permissive microenvironment for myeloma development: a new stromal role for Wnt inhibitor Dkk1. Cancer Res 2012; 72: 2183–2189.
Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD Jr . Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007; 109: 2106–2111.
Ehrlich LA, Chung HY, Ghobrial I, Choi SJ, Morandi F, Colla S et al. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood 2005; 106: 1407–1414.
D'Souza S, del Prete D, Jin S, Sun Q, Huston AJ, Kostov FE et al. Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease. Blood 2011; 118: 6871–6880.
Giuliani N, Colla S, Morandi F, Lazzaretti M, Sala R, Bonomini S 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.
Li B, Shi M, Li J, Zhang H, Chen B, Chen L 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.
Takeuchi K, Abe M, Hiasa M, Oda A, Amou H, Kido S et al. Tgf-Beta inhibition restores terminal osteoblast differentiation to suppress myeloma growth. PLoS One 2010; 5: e9870.
Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M, Pozzi S et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci USA 2010; 107: 5124–5129.
Chantry AD, Heath D, Mulivor AW, Pearsall S, Baud'huin M, Coulton L et al. Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. J Bone Miner Res 2010; 25: 2633–2646.
Mori KJ, Fujitake H, Ohkubo H, Ito Y, Dexter TM . Development of stromal cell colonies in bone marrow cell culture. Gann 1978; 69: 689–693.
Yata K, Yaccoby S . The SCID-rab model: a novel in vivo system for primary human myeloma demonstrating growth of CD138-expressing malignant cells. Leukemia 2004; 18: 1891–1897.
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: 513–523.
Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA 2nd 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.
Chang J, Wang Z, Tang E, Fan Z, McCauley L, Franceschi R et al. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med 2009; 15: 682–689.
Kaneki H, Guo R, Chen D, Yao Z, Schwarz EM, Zhang YE et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 2006; 281: 4326–4333.
Hosen N, Matsuoka Y, Kishida S, Nakata J, Mizutani Y, Hasegawa K et al. CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients. Leukemia 2012; 26: 2135–2141.
Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007; 25: 2464–2472.
Coleman RE . Bisphosphonates: clinical experience. Oncologist 2004; 9 (Suppl 4): 14–27.
Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 2010; 376: 1989–1999.
Wu P, Walker BA, Brewer D, Gregory WM, Ashcroft J, Ross FM et al. A gene expression-based predictor for myeloma patients at high risk of developing bone disease on bisphosphonate treatment. Clin Cancer Res 2011; 17: 6347–6355.
Weinstein RS, Roberson PK, Manolagas SC . Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009; 360: 53–62.
Jain N, Weinstein RS . Giant osteoclasts after long-term bisphosphonate therapy: diagnostic challenges. Nat Rev Rheumatol 2009; 5: 341–346.
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344: 1434–1441.
Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003; 349: 1207–1215.
Tashjian AH Jr, Gagel RF . Teriparatide [human PTH(1–34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res 2006; 21: 354–365.
Pozzi S, Fulciniti M, Yan H, Vallet S, Eda H, Patel K et al. In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma. Bone 2013; 53: 487–496.
Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 2009; 114: 371–379.
Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA . Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int 2010; 21: 1041–1045.
DiMeo TA, Anderson K, Phadke P, Fan C, Perou CM, Naber S et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res 2009; 69: 5364–5373.
Mitra A, Menezes ME, Shevde LA, Samant RS . DNAJB6 induces degradation of beta-catenin and causes partial reversal of mesenchymal phenotype. J Biol Chem 2010; 285: 24686–24694.
Cowling VH, D'Cruz CM, Chodosh LA, Cole MD . c-Myc transforms human mammary epithelial cells through repression of the Wnt inhibitors DKK1 and SFRP1. Mol Cell Biol 2007; 27: 5135–5146.
Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest 2003; 111: 1771–1782.
Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61: 3071–3076.
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA 2002; 99: 14374–14379.
LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 2002; 62: 4996–5000.
Ozaki S, Tanaka O, Fujii S, Shigekiyo Y, Miki H, Choraku M et al. Therapy with bortezomib plus dexamethasone induces osteoblast activation in responsive patients with multiple myeloma. Int J Hematol 2007; 86: 180–185.
Zangari M, Esseltine D, Lee CK, Barlogie B, Elice F, Burns MJ et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol 2005; 131: 71–73.
Acknowledgements
This work was supported in part by a Grants-in-aid for Scientific Research (C) (23591390) from the Ministry of Education, Science, Sport, and Culture of Japan, a National Cancer Center Research and Development Fund (21-8-5) from the Ministry of Health, Labor and Welfare of Japan, and A-STEP from Japan Science and Technology Agency (AS242Z02068Q) to MA, and a Japan Leukemia Research Fund, IMF Japan Aki Horinouchi Research Grant, and a Grant-in-Aid for Scientific Research (21792077, 23659946 and 25463087) from the Ministry of Education, Science, Sport and Culture of Japan to MH. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Leukemia website
Supplementary information
Rights and permissions
About this article
Cite this article
Hiasa, M., Teramachi, J., Oda, A. et al. Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma. Leukemia 29, 207–217 (2015). https://doi.org/10.1038/leu.2014.147
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2014.147
This article is cited by
-
Acute suppression of translation by hyperthermia enhances anti-myeloma activity of carfilzomib
International Journal of Hematology (2024)
-
Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors
International Journal of Hematology (2024)
-
Targeting Pim kinases in hematological cancers: molecular and clinical review
Molecular Cancer (2023)
-
Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents
Journal of Bone and Mineral Metabolism (2023)
-
Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors
International Journal of Hematology (2023)