Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

MULTIPLE MYELOMA, GAMMOPATHIES

Circulating cytokines present in multiple myeloma patients inhibit the osteoblastic differentiation of adipose stem cells

Abstract

Myeloma is characterized by bone lesions, which are related to both an increased osteoclast activity and a defect in the differentiation of medullary mesenchymal stem cells (MSCs) into osteoblasts. Outside the medullary environment, adipocyte-derived MSCs (ASCs) could represent a source of functional osteoblasts. However, we recently found a defect in the osteoblastic differentiation of ASCs from myeloma patients (MM-ASCs). We examined the effects of plasma from myeloma patients at diagnosis (MM-plasmas) and in complete remission (CR-plasmas) and from healthy donors on the osteoblastic differentiation of healthy donor-derived ASCs (HD-ASCs). Osteoblastogenesis in HD-ASCs was suppressed by MM-plasmas. Seven cytokines (ANG1, ENA-78, EGF, PDGF-AA/AB/BB, and TARC) were increased in MM-plasmas and separately inhibited the osteoblastic differentiation of HD-ASCs. Comparison of MM-ASCs and HD-ASCs by RNA sequencing showed that two master genes characterizing adipocyte differentiation, CD36 and PPARγ, were upregulated in MM-ASCs as compared to HD-ASCs. Finally, we demonstrated a significant increase in CD36 and PPARγ expression in HD-ASCs in the presence of MM-plasmas or the seven cytokines individually, similarly as in MM-ASCs. We conclude that specific cytokines in MM-plasmas, besides the well-known DKK1, inhibit the osteoblastic differentiation of MM- and HD-ASCs with a skewing towards adipocyte differentiation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: MM-plasmas inhibit osteoblastic differentiation in HD-ASCs.
Fig. 2: Circulating cytokines in MM-plasmas inhibit osteoblastic differentiation.
Fig. 3: Transcriptome profiles of MM-ASCs and HD-ASCs.
Fig. 4: Cytokines in MM-plasmas enhance adipogenesis-related gene expression.

References

  1. 1.

    Rollig C, Knop S, Bornhauser M. Multiple myeloma. Lancet. 2015;385:2197–208.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  2. 2.

    Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655–64.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Terpos E, Berenson J, Cook RJ, Lipton A, Coleman RE. Prognostic variables for survival and skeletal complications in patients with multiple myeloma osteolytic bone disease. Leukemia. 2010;24:1043–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Terpos E, Morgan G, Dimopoulos MA, Drake MT, Lentzsch S, Raje N, et al. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol. 2013;31:2347–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Adamik J, Galson DL, Roodman GD. Osteoblast suppression in multiple myeloma bone disease. J Bone Oncol. 2018;13:62–70.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Delgado-Calle J, Bellido T, Roodman GD. Role of osteocytes in multiple myeloma bone disease. Curr Opin Support Palliat Care. 2014;8:407–13.

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Lee OL, Horvath N, Lee C, Joshua D, Ho J, Szer J, et al. Bisphosphonate guidelines for treatment and prevention of myeloma bone disease. Intern Med J. 2017;47:938–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Xu S, De Veirman K, De Becker A, Vanderkerken K, Van Riet I. Mesenchymal stem cells in multiple myeloma: a therapeutical tool or target? Leukemia. 2018;32:1500–14.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Barry FP, Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol. 2004;36:568–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013;15:641–8.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Bereziat V, Mazurier C, Auclair M, Ferrand N, Jolly S, Marie T, et al. Systemic dysfunction of osteoblast differentiation in adipose-derived stem cells from patients with multiple myeloma. Cells. 2019; 8: 441.

  12. 12.

    Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Perez Lanzon M, Zini N, et al. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 2015;6:127.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

    Fakhry M, Hamade E, Badran B, Buchet R, Magne D. Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts. World J Stem Cells. 2013;5:136–48.

    PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Raimondo S, Urzi O, Conigliaro A, Bosco GL, Parisi S, Carlisi M, et al. Extracellular vesicle microRNAs contribute to the osteogenic inhibition of mesenchymal stem cells in multiple myeloma. Cancers (Basel). 2020;12:449.

  15. 15.

    Silbermann R, Roodman GD. Myeloma bone disease: Pathophysiology and management. J Bone Oncol. 2013;2:59–69.

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Zhang X, Yuan X, Shi H, Wu L, Qian H, Xu W. Exosomes in cancer: small particle, big player. J Hematol Oncol. 2015;8:83.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Faict S, Muller J, De Veirman K, De Bruyne E, Maes K, Vrancken L, et al. Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts. Blood Cancer J. 2018;8:105.

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Liu Z, Liu H, Li Y, Shao Q, Chen J, Song J, et al. Multiple myeloma-derived exosomes inhibit osteoblastic differentiation and improve IL-6 secretion of BMSCs from multiple myeloma. J Investig Med. 2020;68:45–51.

    PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Raimondo S, Saieva L, Vicario E, Pucci M, Toscani D, Manno M, et al. Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment leading to osteoclastogenesis. J Hematol Oncol. 2019;12:2.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Zhang L, Lei Q, Wang H, Xu C, Liu T, Kong F, et al. Tumor-derived extracellular vesicles inhibit osteogenesis and exacerbate myeloma bone disease. Theranostics. 2019;9:196–209.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Roccaro AM, Sacco A, Maiso P, Azab AK, Tai YT, Reagan M, et al. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest. 2013;123:1542–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Caron M, Auclairt M, Vissian A, Vigouroux C, Capeau J. Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues. Antivir Ther. 2008;13:27–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Wingett SW, Andrews S. FastQ Screen: A tool for multi-genome mapping and quality control. F1000Res. 2018;7:1338.

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    CAS  Article  Google Scholar 

  25. 25.

    Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinforma. 2011;12:323.

    CAS  Article  Google Scholar 

  26. 26.

    Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    CAS  Article  Google Scholar 

  27. 27.

    Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001;125:279–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol. 2001;3:683–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Kaiser M, Mieth M, Liebisch P, Oberlander R, Rademacher J, Jakob C, et al. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur J Haematol. 2008;80:490–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    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;349:2483–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    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;7:585–98.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Podar K, Richardson PG, Hideshima T, Chauhan D, Anderson KC. The malignant clone and the bone-marrow environment. Best Pr Res Clin Haematol. 2007;20:597–612.

    CAS  Article  Google Scholar 

  33. 33.

    Reagan MR, Ghobrial IM. Multiple myeloma mesenchymal stem cells: characterization, origin, and tumor-promoting effects. Clin Cancer Res. 2012;18:342–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Corre J, Mahtouk K, Attal M, Gadelorge M, Huynh A, Fleury-Cappellesso S, et al. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia. 2007;21:1079–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Garderet L, Mazurier C, Chapel A, Ernou I, Boutin L, Holy X, et al. Mesenchymal stem cell abnormalities in patients with multiple myeloma. Leuk Lymphoma. 2007;48:2032–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Ring ES, Lawson MA, Snowden JA, Jolley I, Chantry AD. New agents in the treatment of myeloma bone disease. Calcif Tissue Int. 2018;102:196–209.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Hofmann JN, Landgren O, Landy R, Kemp TJ, Santo L, McShane CM, et al. A prospective study of circulating chemokines and angiogenesis markers and risk of multiple myeloma and its precursor. JNCI Cancer Spectr. 2020;4:pkz104.

    PubMed  Article  Google Scholar 

  38. 38.

    Kline M, Donovan K, Wellik L, Lust C, Jin W, Moon-Tasson L, et al. Cytokine and chemokine profiles in multiple myeloma; significance of stromal interaction and correlation of IL-8 production with disease progression. Leuk Res. 2007;31:591–8.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Zingone A, Wang W, Corrigan-Cummins M, Wu SP, Plyler R, Korde N, et al. Altered cytokine and chemokine profiles in multiple myeloma and its precursor disease. Cytokine. 2014;69:294–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Alexandrakis MG, Sfiridaki A, Miyakis S, Pappa C, Kandidaki E, Alegakis A, et al. Relationship between serum levels of vascular endothelial growth factor, hepatocyte growth factor and matrix metalloproteinase-9 with biochemical markers of bone disease in multiple myeloma. Clin Chim Acta. 2007;379:31–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Karsenty G, Mera P. Molecular bases of the crosstalk between bone and muscle. Bone. 2018;115:43–49.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Giuliani N, Colla S, Lazzaretti M, Sala R, Roti G, Mancini C, et al. Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis. Blood. 2003;102:638–45.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Uneda S, Matsuno F, Sonoki T, Tniguchi I, Kawano F, Hata H. Expressions of vascular endothelial growth factor and angiopoietin-2 in myeloma cells. Haematologica. 2003;88:113–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Giuliani N, Colla S, Morandi F, Rizzoli V. Angiopoietin-1 and myeloma-induced angiogenesis. Leuk Lymphoma. 2005;46:29–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Pappa CA, Tsirakis G, Devetzoglou M, Zafeiri M, Vyzoukaki R. Androvitsanea A, et al. Bone marrow mast cell density correlates with serum levels of VEGF and CXC chemokines ENA-78 and GRO-alpha in multiple myeloma. Tumour Biol. 2014;35:5647–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Tsirakis G, Pappa CA, Kanellou P, Stratinaki MA, Xekalou A, Psarakis FE, et al. Role of platelet-derived growth factor-AB in tumour growth and angiogenesis in relation with other angiogenic cytokines in multiple myeloma. Hematol Oncol. 2012;30:131–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Hock JM, Canalis E. Platelet-derived growth factor enhances bone cell replication, but not differentiated function of osteoblasts. Endocrinology. 1994;134:1423–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Li P, Deng Q, Liu J, Yan J, Wei Z, Zhang Z, et al. Roles for HB-EGF in mesenchymal stromal cell proliferation and differentiation during skeletal growth. J Bone Min Res. 2019;34:295–309.

    CAS  Article  Google Scholar 

  49. 49.

    Lu X, Wang Q, Hu G, Van Poznak C, Fleisher M, Reiss M, et al. ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes Dev. 2009;23:1882–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Aggarwal R, Ghobrial IM, Roodman GD. Chemokines in multiple myeloma. Exp Hematol. 2006;34:1289–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Al-haidari AA, Syk I, Jirstrom K, Thorlacius H. CCR4 mediates CCL17 (TARC)-induced migration of human colon cancer cells via RhoA/Rho-kinase signaling. Int J Colorectal Dis. 2013;28:1479–87.

    PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Liu LB, Xie F, Chang KK, Shang WQ, Meng YH, Yu JJ, et al. Chemokine CCL17 induced by hypoxia promotes the proliferation of cervical cancer cell. Am J Cancer Res. 2015;5:3072–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Zhu F, Li X, Chen S, Zeng Q, Zhao Y, Luo F. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol. 2016;33:17.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  54. 54.

    Yaccoby S, Wezeman MJ, Zangari M, Walker R, Cottler-Fox M, Gaddy D, et al. Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model. Haematologica. 2006;91:192–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Gainor BJ, Buchert P. Fracture healing in metastatic bone disease. Clin Orthop Relat Res. 1983;178:297–302.

  56. 56.

    Gao H, Volat F, Sandhow L, Galitzky J, Nguyen T, Esteve D, et al. CD36 is a marker of human adipocyte progenitors with pronounced adipogenic and triglyceride accumulation potential. Stem Cells. 2017;35:1799–814.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Kawai M, Rosen CJ. PPARgamma: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol. 2010;6:629–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000;20:1868–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Liu Z, Liu H, He J, Lin P, Tong Q, Yang J. Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells. Sci Signal 2020; 13:eaay8203.

  60. 60.

    Bilalis A, Pouliou E, Roussou M, Papanikolaou A, Tassidou A, Economopoulos T, et al. Increased expression of platelet derived growth factor receptor beta on trephine biopsies correlates with advanced myeloma. J BUON. 2017;22:1032–7.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was financially supported by the Institut National de Santé et de Recherche Médicale (INSERM), the Sorbonne University, the Centre de Recherche Saint-Antoine, the Groupement d’Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Intergroupe Francophone du Myélome (IFM) and the Fondation pour la Recherche Médicale (BF, FRM EQU2019 030077868). This work benefited from equipment and services from the iGenSeq (RNA sequencing) and iCONICS (RNAsequence analyses) core facilities of the ICM (Institut du Cerveau et de la Moelle épinière, Hôpital Pitié Salpêtrière, Paris, France). The authors acknowledge the valuable assistance of Romain Morichon of the Sorbonne Université-INSERM, UMR_S938, Centre de Recherche Saint-Antoine Imagery platform.

Author information

Affiliations

Authors

Contributions

Conceptualization, LK, MS, LG; data curation, LK, MA, OP, NF, MZ; formal analysis, LK, MA, OP, MS, LG; funding acquisition, LK, MS, LG; methodology, LK, MA, OP, NF, MZ; supervision, LK, MS, LG; writing of original draft, LK, MS, LG; reviewing and editing, LK, BF, FD, MS, LG.

Corresponding author

Correspondence to Laurent Garderet.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kobari, L., Auclair, M., Piau, O. et al. Circulating cytokines present in multiple myeloma patients inhibit the osteoblastic differentiation of adipose stem cells. Leukemia (2021). https://doi.org/10.1038/s41375-021-01428-6

Download citation

Search

Quick links