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Human osteoclasts differentiated from umbilical cord blood precursors are less prone to apoptotic stimuli than osteoclasts from peripheral blood

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Abstract

Osteoclasts (OCs) are specialized bone-resorbing cells. For “in vitro” analysis, they may be obtained from the precursors present in peripheral blood (PB) or umbilical cord blood (UCB), but there has been no detailed analysis of how the kind of source and cell culture conditions may affect the behavior of these cells. Here we analyzed the behavior of OCs after transfection with specific transcription factor decoy molecules founding that the OCs from PB undergo apoptosis when nuclear factor kappa B (NF-kB) or NFATc1 were removed, or when ERα expression was increased. Conversely, OCs from UCB showed a strong resistance to apoptotic stimuli. We found that survival signals including Bcl-2, Bcl-XL, and Survivin are present in the OCs/UCB, but not in OCs/PB. The resistance to apoptosis seems to be not correlated with NF-kB, NFATc1, or ERα expression level, or with the activation of ERK and Akt proteins. One of the mechanisms responsible for bone remodeling is apoptosis, and being susceptible of therapeutic manipulation, the OCs are extensively employed to investigate cell response to therapies for the treatment of bone loss associated with several diseases, including periodontitis, osteoporosis, and metastatic osteolysis. Therefore, our evidences are to be taken in consideration when both the effects of biological modifiers are tested and OCs apoptosis molecular mechanisms are investigated.

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References

  1. Zaidi M (2007) Skeletal remodeling in health and disease. Nat Med 13:791–801

    Article  PubMed  CAS  Google Scholar 

  2. Tanaka S (2007) Signaling axis in osteoclast biology and therapeutic targeting in the RANKL/RANK/OPG system. Am J Nephrol 27:466–478

    Article  PubMed  Google Scholar 

  3. Tanaka SN, Takahashi, Udagawa N et al (1993) Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest 91:257–263

    Article  PubMed  CAS  Google Scholar 

  4. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342

    Article  PubMed  CAS  Google Scholar 

  5. Wada T, Nakashima T, Hiroshi N, Penninger JM (2006) RANKL–RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12:17–25

    Article  PubMed  CAS  Google Scholar 

  6. Quinn JM, Elliott J, Gillespie MT, Martin TJ (1998) A combination of osteoclast differentiation factor and macrophage-colony stimulating factor is sufficient for both human and mouse osteoclast formation in vitro. Endocrinology 139:4424–4427

    Article  PubMed  CAS  Google Scholar 

  7. Atkins GJ, Kostakis P, Vincent C et al (2006) RANK Expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. J Bone Miner Res 21:1339–1349

    Article  PubMed  CAS  Google Scholar 

  8. Erices A, Conget P, Minguell JJ (2000) Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 109:235–242

    Article  PubMed  CAS  Google Scholar 

  9. Sun B, Jeong YH, Jung JW, Seo K, Lee YS, Kang KS (2007) Regulation of human umbilical cord blood-derived multi-potent stem cells by autogenic osteoclast-based niche-like structure. Biochem Biophys Res Commun 357:92–98

    Article  PubMed  CAS  Google Scholar 

  10. Mann MJ, Dzau VJ (2000) Therapeutic applications of transcription factor decoy oligonucleotides. J Clin Invest 106:1071–1075

    Article  PubMed  CAS  Google Scholar 

  11. Gao H, Xiao J, Sun Q et al (2006) A single decoy oligodeoxynucleotides targeting multiple oncoproteins produces strong anticancer effects. Mol Pharmacol 70:1621–1629

    Article  PubMed  CAS  Google Scholar 

  12. Penolazzi L, Borgatti M, Lambertini E et al (2004) Peptide nucleic acid-DNA decoy chimeras targeting NF-kappaB transcription factors: induction of apoptosis in human primary osteoclasts. Int J Mol Med 14:145–152

    PubMed  CAS  Google Scholar 

  13. Day CJ, Kim MS, Lopez CM, Nicholson GC, Morrison NA (2005) NFAT expression in human osteoclasts. J Cell Biochem 95:17–23

    Article  PubMed  CAS  Google Scholar 

  14. Nakamura T, Imai Y, Matsumoto T et al (2007) Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130:811–823

    Article  PubMed  CAS  Google Scholar 

  15. Piva R, Penolazzi L, Lambertini E, Giordano S, Gambari R (2005) Induction of apoptosis of human primary osteoclasts treated with a transcription factor decoy mimicking a promoter region of estrogen receptor alpha. Apoptosis 10:1079–1094

    Article  PubMed  CAS  Google Scholar 

  16. Matsuzaki K, Katayama K, Takahashi Y et al (1999) Human osteoclast-like cells are formed from peripheral blood mononuclear cells in a coculture with SaOS-2 cells transfected with the parathyroid hormone (PTH)/PTH-related protein receptor gene. Endocrinology 140:925–932

    Article  PubMed  CAS  Google Scholar 

  17. Piva R, Penolazzi L, Zennaro M et al (2006) Induction of apoptosis of osteoclasts by targeting transcription factors with decoy molecules. Ann NY Acad Sci 1091:509–516

    Article  PubMed  CAS  Google Scholar 

  18. Penolazzi L, Zennaro M, Lambertini E et al (2007) Induction of estrogen receptor alpha expression with decoy oligonucleotide targeted to NFATc1 binding sites in osteoblasts. Mol Pharmacol 71:1457–1462

    Article  PubMed  CAS  Google Scholar 

  19. Evans CE, Mylchreest S, Andrew JG (2006) Age of donor alters the effect of cyclic hydrostatic pressure on production by human macrophages and osteoblasts of sRANKL, OPG and RANK. BMC Musculoskelet Disord 7:21

    Article  PubMed  CAS  Google Scholar 

  20. Asagiri M, Takayanagi H (2007) The molecular understanding of osteoclast differentiation. Bone 40:251–264

    Article  PubMed  CAS  Google Scholar 

  21. Bruzzaniti A, Baron R (2006) Molecular regulation of osteoclast activity. Rev Endocr Metab Disord 7:123–139

    Article  PubMed  CAS  Google Scholar 

  22. Strasser A, O’Connor L, Dixit VM (2000) Apoptosis signaling. Annu Rev Biochem 69:217–245

    Article  PubMed  CAS  Google Scholar 

  23. Akiyama T, Bouillet P, Miyazaki T et al (2003) Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. EMBO J 22:6653–6664

    Article  PubMed  CAS  Google Scholar 

  24. Sevilla L, Zaldumbide A, Carlotti F, Dayem MA, Pognonec P, Boulukos KE (2001) Bcl-XL expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1. J Biol Chem 276:17800–17807

    Article  PubMed  CAS  Google Scholar 

  25. Tamm I, Wang Y, Sausville E et al (1998) IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 58:5315–5320

    PubMed  CAS  Google Scholar 

  26. Gingery A, Bradley E, Shaw A, Oursler MJ (2003) Phosphatidylinositol 3-kinase coordinately activates the MEK/ERK and AKT/NFkappaB pathways to maintain osteoclast survival. J Cell Biochem 89:165–179

    Article  PubMed  CAS  Google Scholar 

  27. Stern PH (2007) Antiresorptive agents and osteoclast apoptosis. J Cell Bioch 101:1087–1096

    Article  CAS  Google Scholar 

  28. Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442

    Article  PubMed  CAS  Google Scholar 

  29. Brandwood CP, Hoyland JA, Hillarby MC et al (2003) Apoptotic gene expression in Paget’s disease: a possible role for Bcl-2. J Pathol 201:504–512

    Article  PubMed  CAS  Google Scholar 

  30. Hentunen TA, Reddy SV, Boyce BF et al (1998) Immortalization of osteoclast precursors by targeting Bcl-XL and Simian virus 40 large T antigen to the osteoclast lineage in transgenic mice. J Clin Invest 102:88–97

    Article  PubMed  CAS  Google Scholar 

  31. Zhang Q, Badell IR, Schwarz EM et al (2005) Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2. Arthritis Rheum 52:2708–2718

    Article  PubMed  CAS  Google Scholar 

  32. Shin S, Sung BJ, Cho YS et al (2001) An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 40:1117–1123

    Article  PubMed  CAS  Google Scholar 

  33. Ahn KS, Sethi G, Chao TH et al (2007) Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products. Blood 110:2286–2295

    Article  PubMed  CAS  Google Scholar 

  34. Bharti AC, Aggarwal BB (2004) Ranking the role of RANK ligand in apoptosis. Apoptosis 9:677–690

    Article  PubMed  CAS  Google Scholar 

  35. Hodge MJ, Kirkland MA, Nicholson G (2007) Multiple roles of M-CSF in human osteoclastogenesis. J Cell Biochem 102:759–768

    Article  PubMed  CAS  Google Scholar 

  36. Felix R, Hofstetter W, Wetterwald A, Cecchini MG, Fleisch H (1994) Role of colony-stimulating factor-1 in bone metabolism. J Cel Bioch 55:340–349

    Article  CAS  Google Scholar 

  37. Bharti AC, Takada Y, Shishodia S, Aggarwal BB (2004) Evidence that receptor activator of nuclear factor (NF)-kappaB ligand can suppress cell proliferation and induce apoptosis through activation of a NF-kappaB independent and TRAF6-dependent mechanism. J Biol Chem 279:6065–6076

    Article  PubMed  CAS  Google Scholar 

  38. Del Fattore A, Teti A, Rucci N (2008) Osteoclast receptors and signaling. Arch Biochem Biophys. doi:10.1016/j.abb.2008.01.011 (In press)

  39. Lamoureux F, Richard P, Wittrant Y et al (2007) Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption. Cancer Res 67:7308–7318

    Article  PubMed  CAS  Google Scholar 

  40. Hettinger K, Vikhanskaya F, Poh MK et al (2007) c-Jun promotes cellular survival by suppression of PTEN. Cell Death Differ 14:218–229

    Article  PubMed  CAS  Google Scholar 

  41. Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA (2003) M-CSF, TNFa and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ 10:1165–1177

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by grants from MIUR FIRB-2001, MIUR COFIN-2005, STAMINA project, Fondazione Cassa di Risparmio di Padova e Rovigo. E.L. is a recipient of a fellowship from Fondazione Cassa di Risparmio di Cento.

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Authors and Affiliations

  1. Molecular Biology Section, Department of Biochemistry and Molecular Biology, Ferrara University, Via Fossato di Mortara, 74, Ferrara, 44100, Italy

    Letizia Penolazzi, Barbara Pocaterra, Elisa Tavanti, Elisabetta Lambertini, Roberto Gambari & Roberta Piva

  2. Section of Obstetric and Gynaecological Clinic, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara, 44100, Italy

    Fortunato Vesce

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  1. Letizia Penolazzi
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  2. Barbara Pocaterra
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  3. Elisa Tavanti
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  4. Elisabetta Lambertini
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  5. Fortunato Vesce
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  6. Roberto Gambari
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  7. Roberta Piva
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Correspondence to Roberta Piva.

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Penolazzi, L., Pocaterra, B., Tavanti, E. et al. Human osteoclasts differentiated from umbilical cord blood precursors are less prone to apoptotic stimuli than osteoclasts from peripheral blood. Apoptosis 13, 553–561 (2008). https://doi.org/10.1007/s10495-008-0188-7

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  • DOI: https://doi.org/10.1007/s10495-008-0188-7

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