Abstract
The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast (OCL) formation and bone lesions is still unknown. Osteocytes regulate bone remodelling at least partially, as a result of their cell death triggering OCL recruitment. In this study, we found that the number of viable osteocytes was significantly smaller in MM patients than in healthy controls, and negatively correlated with the number of OCLs. Moreover, the MM patients with bone lesions had a significantly smaller number of viable osteocytes than those without, partly because of increased apoptosis. These findings were further confirmed by ultrastructural in vitro analyses of human preosteocyte cells cocultured with MM cells, which showed that MM cells increased preosteocyte death and apoptosis. A micro-array analysis showed that MM cells affect the transcriptional profiles of preosteocytes by upregulating the production of osteoclastogenic cytokines such as interleukin (IL)-11, and increasing their pro-osteoclastogenic properties. Finally, the osteocyte expression of IL-11 was higher in the MM patients with than in those without bone lesions. Our data suggest that MM patients are characterized by a reduced number of viable osteocytes related to the presence of bone lesions, and that this is involved in MM-induced OCL formation.
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References
Roodman GD . Pathogenesis of myeloma bone disease. Leukemia 2009; 23: 435–441.
Giuliani N, Colla S, Rizzoli V . New insight in the mechanism of osteoclast activation and formation in multiple myeloma: focus on the receptor activator of NF-kappaB ligand (RANKL). Exp Hematol 2004; 32: 685–691.
Giuliani N, Rizzoli V, Roodman GD . Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood 2006; 108: 3992–3996.
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.
Roodman GD, Choi SJ . MIP-1 alpha and myeloma bone disease. Cancer Treat Res 2004; 118: 83–100.
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.
Choi SJ, Cruz JC, Craig F, Chung H, Devlin RD, Roodman GD et al. Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 2000; 96: 671–675.
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.
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.
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.
Standal T, Abildgaard N, Fagerli UM, Stordal B, Hjertner O, Borset M et al. HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood 2007; 109: 3024–3030.
Heino TJ, Hentunen TA . Differentiation of osteoblasts and osteocytes from mesenchymal stem cells. Curr Stem Cell Res Ther 2008; 3: 131–145.
Bonewald LF . The amazing osteocyte. J Bone Miner Res 2011; 26: 229–238.
Palumbo C, Ferretti M, Ardizzoni A, Zaffe D, Marotti G . Osteocyte-osteoclast morphological relationships and the putative role of osteocytes in bone remodeling. J Musculoskelet Neuronal Interact 2001; 1: 327–332.
Teti A, Zallone A . Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. Bone 2009; 44: 11–16.
Noble BS, Reeve J . Osteocyte function, osteocyte death and bone fracture resistance. Mol Cell Endocrinol 2000; 159: 7–13.
Gu G, Mulari M, Peng Z, Hentunen TA, Väänänen HK . Death of osteocytes turns off the inhibition of osteoclasts and triggers local bone resorption. Biochem Biophys Res Commun 2005; 335: 1095–1101.
Zhao S, Zhang YK, Harris S, Ahuja SS, Bonewald LF . MLO-Y4 osteocyte-like cells support osteoclast formation and activation. J Bone Miner Res 2002; 17: 2068–2079.
Kogianni G, Mann V, Noble BS . Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction. J Bone Miner Res 2008; 23: 915–927.
van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 2004; 199: 805–814.
Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003; 22: 6267–6276.
Tomkinson A, Reeve J, Shaw RW, Noble BS . The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. J Clin Endocrinol Metab 1997; 82: 3128–3135.
Emerton KB, Hu B, Woo AA, Sinofsky A, Hernandez C, Majeska RJ et al. Osteocyte apoptosis and control of bone resorption following ovariectomy in mice. Bone 2010; 46: 577–583.
Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC . Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 1998; 102: 274–282.
O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004; 145: 1835–1841.
Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab 2007; 5: 464–475.
Bodine PV, Vernon SK, Komm BS . Establishment and hormonal regulation of a conditionally transformed preosteocytic cell line from adult human bone. Endocrinology 1996; 137: 4592–4604.
Busse B, Djonic D, Milovanovic P, Hahn M, Püschel K, Ritchie RO et al. Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell 2010; 9: 1065–1075.
Eisenberger S, Ackermann K, Voggenreiter G, Sültmann H, Kasperk C, Pyerin W . Metastases and multiple myeloma generate distinct transcriptional footprints in osteocytes in vivo. J Pathol 2008; 214: 617–626.
Bataille R, Chappard D, Basle MF . Quantifiable excess of bone resorption in monoclonal gammopathy is an early symptom of malignancy: a prospective study of 87 bone biopsies. Blood 1996; 87: 4762–4769.
Libouban H, Moreau MF, Baslé MF, Bataille R, Chappard D . Selection of a highly aggressive myeloma cell line by an altered bone microenvironment in the C57BL/KaLwRij mouse. Biochem Biophys Res Commun 2004; 316: 859–866.
Libouban H, Moreau MF, Baslé MF, Bataille R, Chappard D . Increased bone remodeling due to ovariectomy dramatically increases tumoral growth in the 5T2 multiple myeloma mouse model. Bone 2003; 33: 283–292.
Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T . Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 1999; 104: 1363–1374.
Ahuja SS, Zhao S, Bellido T, Plotkin LI, Jimenez F, Bonewald LF . CD40 ligand blocks apoptosis induced by tumor necrosis factor alpha, glucocorticoids, and etoposide in osteoblasts and the osteocyte-like cell line murine long bone osteocyte-Y4. Endocrinology 2003; 144: 1761–1769.
Boukhechba F, Balaguer T, Michiels JF, Ackermann K, Quincey D, Bouler JM et al. Human primary osteocyte differentiation in a 3D culture system. J Bone Miner Res 2009; 24: 1927–1935.
Giuliani N, Colla S, Morandi F, Rizzoli V . The RANK/RANK ligand system is involved in interleukin-6 and interleukin-11 up-regulation by human myeloma cells in the bone marrow microenvironment. Haematologica 2004; 89: 1118–1123.
Hjertner O, Torgersen ML, Seidel C, Hjorth-Hansen H, Waage A, Børset M et al. Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: a possible role for HGF in myeloma-associated osteolytic bone disease. Blood 1999; 94: 3883–3888.
Girasole G, Passeri G, Jilka RL, Manolagas SC . Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest 1994; 93: 1516–1524.
Romas E, Udagawa N, Zhou H, Tamura T, Saito M, Taga T et al. The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. J Exp Med 1996; 183: 2581–2591.
Sotiriou C, Lacroix M, Lespagnard L, Larsimont D, Paesmans M, Body JJ . Interleukins-6 and -11 expression in primary breast cancer and subsequent development of bone metastases. Cancer Lett 2001; 169: 87–95.
Zhang Y, Fujita N, Oh-hara T, Morinaga Y, Nakagawa T, Yamada M et al. Production of interleukin-11 in bone-derived endothelial cells and its role in the formation of osteolytic bone metastasis. Oncogene 1998; 16: 693–703.
Morgan H, Tumber A, Hill PA . Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. Int J Cancer 2004; 109: 653–660.
Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA . Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 2003; 32: 1–7.
Okuyama N, Matsumine A, Kosugi R, Wakabayashi H, Uchida A . Matrix metalloproteinase-1 is a crucial bone metastasis factor in a human breast cancer-derived highly invasive cell line. Oncol Rep 2008; 20: 1497–1504.
Eck SM, Hoopes PJ, Petrella BL, Coon CI, Brinckerhoff CE . Matrix metalloproteinase-1 promotes breast cancer angiogenesis and osteolysis in a novel in vivo model. Breast Cancer Res Treat 2009; 116: 79–90.
Barillé S, Akhoundi C, Collette M, Mellerin MP, Rapp MJ, Harousseau JL et al. Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. Blood 1997; 90: 1649–1655.
Terpos E, Christoulas D, Katodritou E, Bratengeier C, Gkotzamanidou M, Michalis E et al. Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma; reduction post-bortezomib monotherapy. Int J Cancer 2011; e-pub ahead of print 2 November 2011; doi: 10.1002/ijc.27342.
Brunetti G, Oranger A, Mori G, Specchia G, Rinaldi E, Curci P et al. Sclerostin is overexpressed by plasma cells from multiple myeloma patients. Ann NY Acad Sci 2011; 1237: 19–23.
Mabilleau G, Mieczkowska A, Edmonds ME . Thiazolidinediones induce osteocyte apoptosis and increase sclerostin expression. Diabet Med 2010; 27: 925–932.
Vincent C, Findlay DM, Welldon KJ, Wijenayaka AR, Zheng TS, Haynes DR et al. Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFalpha induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts. J Bone Miner Res 2009; 24: 1434–1449.
Cheung WY, Simmons CA, You L . Osteocyte apoptosis regulates osteoclast precursor adhesion via osteocytic IL-6 secretion and endothelial ICAM-1 expression. Bone 2011; e-pub ahead of print 1 October 2011.
Shandala T, Ng YS, Hopwood B, Yip YC, Foster BK, Xian CJ . The role of osteocyte apoptosis in cancer chemotherapy-induced bone loss. J Cell Physiol 2011; e-pub ahead of print 21 September 2011.
Al-Dujaili SA, Lau E, Al-Dujaili H, Tsang K, Guenther A, You L . Apoptotic osteocytes regulate osteoclast precursor recruitment and differentiation in vitro. J Cell Biochem 2011; 112: 2412–2423.
Berenson JR . Therapeutic options in the management of myeloma bone disease. Semin Oncol 2010; 37 (Suppl 1): S20–S29.
Terpos E, Sezer O, Croucher PI, GarcÃa-Sanz R, Boccadoro M, San Miguel J et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 2009; 20: 1303–1317.
Bellido T, Plotkin LI . Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone 2010; 49: 50–55.
Acknowledgements
This study was supported by grants from the International Myeloma Foundation, the Italian Ministry of Health (Progetti Regione Emilia Romagna), and the Associazione Italiana per la Ricerca sul Cancro (AIRC: N.G.: IG2099 No. 8530; A.N.: IG4569 and Special Program Molecular Clinical Oncology 5 per mille No. 9965). We would like to thank Professor David Roodman for critically reviewing the manuscript, and Judy Anderson and Ken Patrene for their technical support.
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Giuliani, N., Ferretti, M., Bolzoni, M. et al. Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation. Leukemia 26, 1391–1401 (2012). https://doi.org/10.1038/leu.2011.381
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DOI: https://doi.org/10.1038/leu.2011.381
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