Effect of Notch1 signaling abnormality on the pathogenesis of myeloma bone disease

doi:10.3969/j.issn.2095-4344.2014.14.001

Abstract

Abstract:

BACKGROUND: The pathogenesis of multiple myeloma bone disease is far from elucidated. The impaired osteogenic differentiation of bone marrow mesenchymal stem cells leads to osteoblast deficiency. Notch1 signaling has a key role in the proliferation and differentiation of bone marrow mesenchymal stem cells.
OBJECTIVE: To explore the role of Notch1 signaling in the pathogenesis of myeloma bone disease.
METHODS: Bone marrow mesenchymal stem cells from myeloma patients and normal donors were isolated and cultured. The expressions of Notch1 and osteogenic marker Runx2 were detected with real-time PCR and western blot before and after osteogenic induction. Von kossa staining was employed to detect calcium deposition. DAPT, an inhibitor of notch1 signaling, and placebo were added to the osteogenic medium of bone marrow mesenchymal stem cells, respectively. The expression of Hes1, a downstream gene of Notch1 signaling, and Runx2 were tested using real-time PCR and western blot after 48 hours. Von kossa staining was used to detect calcium deposition after 2 weeks.
RESULTS AND CONCLUSION: After cultured in osteogenic medium for 48 hours, Notch1 expression of bone marrow mesenchymal stem cells from myeloma patients decreased, which was not as much as that of bone marrow mesenchymal stem cells from normal donors. This was accompanied by much more decreased expression of Runx2 and calcium deposition in the bone marrow mesenchymal stem cells from myeloma patients compared with those from normal donors. Addition of DAPT inhibited Hes1 and enhanced Runx2 expression after 48 hours, which was accompanied with more calcium deposition in bone marrow mesenchymal stem cells from myeloma patients after 2 weeks. These experimental data above suggest that the deactivation of Notch1 signaling is blocked, which is possibly related to the impaired osteogenic differentiation potential in the bone marrow mesenchymal stem cells from myeloma patients.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

全文链接：

Key words: bone marrow, mesenchymal stem cells, multiple myeloma, osteoblasts, cell proliferation

CLC Number:

R394.2

Zhu Hong-yan, Wang Qian, Li Ya-li, Ge Xue-ping, Chen Ping, Li Bing-zong. Effect of Notch1 signaling abnormality on the pathogenesis of myeloma bone disease[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(14): 2133-2139.

Figures/Tables 4

References

[1] Alegre A, Gironella M, Bailén A, et al. Zoledronic acid in the management of bone disease as a consequence of multiple myeloma: a review. Eur J Haematol. 2013 Dec 14.
[2] Giuliani N, Bataille R, Mancini C, et al. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood. 2001; 98(13):3527-3533.
[3] 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(1): 334-338.
[4] Horwitz EM, Le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393-395.
[5] Reagan MR, Ghobrial IM. Multiple myeloma mesenchymal stem cells: characterization, origin, and tumor-promoting effects. Clin Cancer Res. 2012;18(2):342-349.
[6] Giuliani N, Mangoni M, Rizzoli V. Osteogenic differentiation of mesenchymal stem cells in multiple myeloma: identification of potential therapeutic targets. Exp Hematol. 2009;37(8):879-886.
[7] Wharton KA, Yedvobnick B, Finnerty VG, et al. opa: a novel family of transcribed repeats shared by the Notch locus and other developmentally regulated loci in D. melanogaster. Cell. 1985;40(1):55-62.
[8] Xu N, Liu H, Qu F, et al. Hypoxia inhibits the differentiation of mesenchymal stem cells into osteoblasts by activation of Notch signaling. Exp Mol Pathol. 2013;94(1):33-39.
[9] Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003; 121(5):749-757.
[10] Chen Z, Orlowski RZ, Wang M, et al. Osteoblastic niche supports the growth of quiescent multiple myeloma cells. Blood. 2014;123(14):2204-2208.
[11] Sezer O. Myeloma bone disease: recent advances in biology, diagnosis, and treatment. Oncologist. 2009;14(3):276-283.
[12] Galson DL, Silbermann R, Roodman GD. Mechanisms of multiple myeloma bone disease. Bonekey Rep. 2012;1:135.
[13] Roodman GD. Osteoblast function in myeloma. Bone. 2011; 48(1):135-140.
[14] 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(12): 2323-2329.
[15] Zhou F, Meng S, Song H, et al. Dickkopf-1 is a key regulator of myeloma bone disease: opportunities and challenges for therapeutic intervention. Blood Rev. 2013;27(6):261-267.
[16] Kristensen IB, Christensen JH, Lyng MB, et al. Expression of osteoblast and osteoclast regulatory genes in the bone marrow microenvironment in multiple myeloma: only up-regulation of Wnt inhibitors SFRP3 and DKK1 is associated with lytic bone disease. Leuk Lymphoma. 2014; 55(4):911-919.
[17] Tsirakis G, Roussou P, Pappa CA, et al. Increased serum levels of MIP-1alpha correlate with bone disease and angiogenic cytokines in patients with multiple myeloma. Med Oncol. 2014;31(1):778.
[18] 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(7):2472-2483.
[19] Mohty M, Malard F, Mohty B, et al. The effects of bortezomib on bone disease in patients with multiple myeloma. Cancer. 2014;120(5):618-623.
[20] Qiang YW, Heuck CJ, Shaughnessy JD, et al. Proteasome inhibitors and bone disease. Semin Hematol. 2012;49(3): 243-248.
[21] Zangari M, Terpos E, Zhan F, et al. Impact of bortezomib on bone health in myeloma: a review of current evidence. Cancer Treat Rev. 2012;38(8):968-980.
[22] 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(2):491-504.
[23] Qiang YW, Hu B, Chen Y, et al. Bortezomib induces osteoblast differentiation via Wnt-independent activation of beta-catenin/TCF signaling. Blood. 2009;113(18):4319-4330.
[24] Tan T, Lu B, Zhang J, et al. Notch1 Signaling Antagonizes Transforming Growth Factor-β Pathway and Induces Apoptosis in Rabbit Trophoblast Stem Cells. Stem Cells Dev. 2014;23(8):813-822.
[25] Mirandola L, Apicella L, Colombo M, et al. Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1. Leukemia. 2013;27(7):1558-1566.
[26] Guo D, Li C, Teng Q, et al. Notch1 overexpression promotes cell growth and tumor angiogenesis in myeloma. Neoplasma. 2013;60(1):33-40.
[27] Nefedova Y, Cheng P, Alsina M, et al. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood. 2004;103(9):3503-3510.
[28] Boopathy AV, Pendergrass KD, Che PL, et al. Oxidative stress-induced Notch1 signaling promotes cardiogenic gene expression in mesenchymal stem cells. Stem Cell Res Ther. 2013;4(2):43.
[29] Hilton MJ, Tu X, Wu X, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008;14(3):306-314.
[30] Jung SR, Song NJ, Yang DK, et al. Silk proteins stimulate osteoblast differentiation by suppressing the Notch signaling pathway in mesenchymal stem cells. Nutr Res. 2013; 33(2): 162-170.
[31] Schwarzer R, Kaiser M, Acikgoez O, et al. Notch inhibition blocks multiple myeloma cell-induced osteoclast activation. Leukemia. 2008;22(12):2273-2277.