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Bisphosphonates: effects on osteoblast

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Abstract

Purpose

Bisphosphonates are synthetic analogues of pyrophosphate usually used in treating bone disorders such as osteoporosis, Paget’s disease, fibrous dysplasia, hypercalcemia of malignancy, and inflammation-related bone loss. Though therapeutic effects of bisphosphonates depend primarily on their inhibitory effect on osteoclasts, increasing attention is being given to other effector cells, such as osteoblasts. This review focuses on the presumed effect of bisphosphonates on osteoblasts.

Methods

A review of the literature was conducted to evaluate the pharmacodynamic effects of bisphosphonates including inhibition of osteoclasts and apoptosis of osteocytes and osteoblasts as well as their potential stimulatory effects on the proliferation of osteoblasts.

Results

Studies have demonstrated that bisphosphonates may stimulate proliferation of osteoblasts and inhibit apoptosis of osteocytes and osteoblasts.

Conclusion

Considering that osteoblasts may be involved in bone disorders, such as osteoporosis, osteopetrosis, osteogenesis imperfecta, and Paget’s disease, and that bisphosphonates may stimulate proliferation of osteoblasts and inhibit apoptosis of osteocytes and osteoblasts, it is conceivable that a role for bisphosphonates exists in these diseases beyond merely the osteoclast influence.

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References

  1. Ralston SH, Hacking L, Willocks L, Bruce F, Pitkeathly DA (1989) Clinical, biochemical, and radiographic effects of aminohydroxypropylidene bisphosphonate treatment in rheumatoid arthritis. Ann Rheum Dis 48:396–399

    Article  PubMed  CAS  Google Scholar 

  2. Eggelmeijer F, Papapoulos SE, van Paassen HC, Dijkmans BA, Breedveld FC (1994) Clinical and biochemical response to single infusion of pamidronate in patients with active rheumatoid arthritis: a double blind placebo controlled study. J Rheumatol 21:2016–2020

    PubMed  CAS  Google Scholar 

  3. Lala R, Matarazzo P, Bertelloni S, Buzi F, Rigon F, de Sanctis C (2000) Pamidronate treatment of bone fibrous dysplasia in nine children with McCune-Albright syndrome. Acta Paediatr 89:188–193

    Article  PubMed  CAS  Google Scholar 

  4. Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289:1508–1514

    Article  PubMed  CAS  Google Scholar 

  5. Lane JM, Khan SN, O’Connor WJ et al (2001) Bisphosphonate therapy in fibrous dysplasia. Clin Orthop 382:6–12

    Article  PubMed  Google Scholar 

  6. Reszka AA, Rodan GA (2004) Nitrogen-containing bisphosphonate mechanism of action. Mini Rev Med Chem 4:711–719

    PubMed  CAS  Google Scholar 

  7. Frith JC, Monkkonen J, Blackburn GM, Russell RG, Rogers MJ (1997) Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5’-(beta, gammadichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res 12:1358–1367

    Article  PubMed  CAS  Google Scholar 

  8. Frith JC, Monkkonen J, Auriola S, Monkkonen H, Rogers MJ (2001) The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 44:2201–2210

    Article  PubMed  CAS  Google Scholar 

  9. Rogers MJ (2003) New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 9:2643–2658

    Article  PubMed  CAS  Google Scholar 

  10. Sato M, Grasser W (1990) Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. J Bone Miner Res 5:31–39

    Article  PubMed  CAS  Google Scholar 

  11. Sato M, Grasser W, Endo N et al (1991) Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 88:2095–2105

    Article  PubMed  CAS  Google Scholar 

  12. Murakami H, Takahashi N, Sasaki T et al (1995) A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders. Bone 17:137–144

    Article  PubMed  CAS  Google Scholar 

  13. Zimolo Z, Wesolowski G, Rodan GA (1995) Acid extrusion is induced by osteoclast attachment to bone. Inhibition by alendronate and calcitonin. J Clin Invest 96:2277–2283

    Article  PubMed  CAS  Google Scholar 

  14. Rodan GA, Fleisch HA (1996) Bisphosphonates: mechanisms of action. J Clin Invest 97:2692–2696

    Article  PubMed  CAS  Google Scholar 

  15. Tsuchimoto M, Azuma Y, Higuchi O et al (1994) Alendronate modulates osteogenesis of human osteoblastic cell in vitro. Jpn J Pharmacol 66:25–33

    Article  PubMed  CAS  Google Scholar 

  16. Giuliani N, Girasole G, Pedrazzoni M, Passeri G, Gatti C, Passeri M (1995) Alendronate stimulates b-FGF production and mineralized nodule formation in human osteoblastic cells and osteoblastogenesis in human bone marrow cultures. J Bone Miner Res 10:S171

    Google Scholar 

  17. Gallagher JA, Gundle R, Beresford JN (1998) Isolation and culture of bone-forming cells (osteoblasts) from human bone. In: Jones GE (ed) Methods in molecular medicine: human cell culture protocols. Humana, Totowa, pp 233–262

    Google Scholar 

  18. Giuliani N, Pedrazzoni M, Negri G, Passeri G, Impicciatore M, Girasole G (1998) Biphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone 22:455–461

    Article  PubMed  CAS  Google Scholar 

  19. Mathov I, Plotkin LI, Sgarlata CL, Leoni J, Bellido T (2001) Extracellular signal-regulated kinases and calcium channels are involved in the proliferative effect of bisphosphonates on osteoblastic cells in vitro. J Bone Miner Res 16:2050–2056

    Article  PubMed  CAS  Google Scholar 

  20. Viereck V, Emons G, Lauck V et al (2002) Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun 291:680–686

    Article  PubMed  CAS  Google Scholar 

  21. Im G, Qureshi SA, Kenney J, Rubash HE, Shanbhag AS (2004) Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 25:4105–4115

    Article  PubMed  CAS  Google Scholar 

  22. Mackie EJ (2003) Osteoblasts: novel roles in orchestration of skeletal architecture. Int J Biochem Cell Biol 35:1301–1305

    Article  PubMed  CAS  Google Scholar 

  23. Kim HH, Lee DE, Shin JN et al (1999) Receptor activator of NF-kB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett 443:297–302

    Article  PubMed  CAS  Google Scholar 

  24. Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M (2000) Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kB ligand (RANKL). J Biol Chem 275:31155–31161

    Article  PubMed  CAS  Google Scholar 

  25. Kobayashi N, Kadono Y, Naito A et al (2001) Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J 20:1271–1280

    Article  PubMed  CAS  Google Scholar 

  26. Simonet WS, Lacey DL, Dunstan CR et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319

    Article  PubMed  CAS  Google Scholar 

  27. Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1999) Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25:255–259

    Article  PubMed  CAS  Google Scholar 

  28. Abu-Amer Y, Erdmann J, Kollias G, Alexopoulou L, Ross FP, Teitelbaum SL (2000) Tumor necrosis factor receptors types 1 and 2 differentially regulate osteoclastogenesis. J Biol Chem 275:27307–27310

    PubMed  CAS  Google Scholar 

  29. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL (2000) TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 106:1481–1488

    Article  PubMed  CAS  Google Scholar 

  30. Kaji K, Katogi R, Azuma Y, Naito A, Inoue JI, Kudo A (2001) Tumor necrosis factor alpha-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6. J Bone Miner Res 16:1593–1599

    Article  PubMed  CAS  Google Scholar 

  31. Zou W, Hakim I, Tschoep K, Endres S, Bar-Shavit X (2001) Tumor necrosis factor-a mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism. J Cell Biochem 83:70–83

    Article  PubMed  CAS  Google Scholar 

  32. Nakao A, Fukushima H, Kajiya H, Ozeki S, Okabe K (2007) RANKL-stimulated TNFa production in osteoclast precursor cells promotes osteoclastogenesis by modulating RANK signaling pathways. Biochem Biophys Res Commun 357:945–950

    Article  PubMed  CAS  Google Scholar 

  33. Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL (2005) IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115:282–290

    PubMed  CAS  Google Scholar 

  34. Yoshida H, Hayashi S, Kunisada T et al (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345:442–444

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  36. Faccio R, Takeshita S, Zallone A, Ross FP, Teitelbaum SL (2003) c-Fms and the αvβ3 integrin collaborate during osteoclast differentiation. J Clin Invest 111:749–758

    PubMed  CAS  Google Scholar 

  37. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL (1999) Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140:4367–4370

    Article  PubMed  CAS  Google Scholar 

  38. Troen BR (2003) Molecular mechanisms underlying osteoclast formation and activation. Exp Gerontol 38:605–614

    Article  PubMed  CAS  Google Scholar 

  39. Zaidi M, Blair HC, Moonga BS, Abe E, Huang CL (2003) Osteoclastogenesis, bone resorption, and osteoclast-based therapeutics. J Bone Miner Res 18:599–609

    Article  PubMed  Google Scholar 

  40. Lajeunesse D, Busque L, Menard P, Brunette MG, Bonny Y (1996) Demonstration of an osteoblast defect in two cases of human malignant osteopetrosis. Correction of the phenotype after bone marrow transplant. J Clin Invest 98:1835–1842

    Article  PubMed  CAS  Google Scholar 

  41. Glorieux FH, Rauch F, Plotkin H et al (2000) Type v osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 15:1650–1658

    Article  PubMed  CAS  Google Scholar 

  42. Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R (2002) Osteogenesis imperfecta type vi: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 17:30–38

    Article  PubMed  Google Scholar 

  43. Labuda M, Morissette J, Ward LM et al (2002) Osteogenesis imperfecta type vii maps to the short arm of chromosome 3. Bone 31:19–25

    Article  PubMed  CAS  Google Scholar 

  44. Ward LM, Rauch F, Travers R et al (2002) Osteogenesis imperfecta type vii: an autosomal recessive form of brittle bone disease. Bone 31:12–18

    Article  PubMed  CAS  Google Scholar 

  45. Bender IB (2003) Paget's disease. J Endod 29:720–723

    Article  PubMed  CAS  Google Scholar 

  46. Siris ES, Roodman GD (2003) Paget’s disease. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research, Chicago, pp 495–508

  47. Menaa C, Reddy SV, Kurihara N et al (2000) Enhanced rank ligand expression and responsivity of bone marrow cells in Paget's disease of bone. J Clin Invest 105:1833–1888

    Article  PubMed  CAS  Google Scholar 

  48. Neale SD, Smith R, Wass JA, Athanasou NA (2000) Osteoclast differentiation from circulating mononuclear precursors in Paget's disease is hypersensitive to 1,25-dihydroxyvitamin d(3) and RANKL. Bone 27:409–416

    Article  PubMed  CAS  Google Scholar 

  49. Buckley KA, Fraser WD (2002) Receptor activator for nuclear factor kappaB ligand and osteoprotegerin: regulators of bone physiology and immune responses/potential therapeutic agents and biochemical markers. Ann Clin Biochem 39:551–556

    Article  PubMed  CAS  Google Scholar 

  50. Sahni M, Guenther HL, Fleisch H, Collin P, Martin TJ (1993) Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J Clin Invest 91:2004–2011

    Article  PubMed  CAS  Google Scholar 

  51. Nishikawa M, Akatsu T, Katayama Y, Yasutomo Y, Kado S, Kugal N, Yamamoto M, Nagata N (1996) Bisphosphonates act on osteoblastic cells and inhibit osteoclast formation in mouse marrow cultures. Bone 18:9–14

    Article  PubMed  CAS  Google Scholar 

  52. Russell RG, Rogers MJ, Frith JC, Luckman SP, Coxon FP, Benford HL, Croucher PI, Shipman C, Fleisch HA (1999) The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res 2:53–65

    Article  Google Scholar 

  53. Viereck V, Emons G, Lauck V, Frosch KH, Blaschke S, Grundker C, Hofbauer LC (2002) Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun 291:680–686

    Article  PubMed  CAS  Google Scholar 

  54. Pan B, Farrugia AN, To LB, FindlayDM GJ, Lynch K, Zannettino AC (2004) The nitrogen containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-alpha converting enzyme (TACE). J Bone Miner Res 19:147–154

    Article  PubMed  CAS  Google Scholar 

  55. Kim HK, Kim JH, Abbas AA, Yoon TR (2009) Alendronate enhances osteogenic differentiation of bone marrow stromal cells: a preliminary study. Clin Orthop Relat Res 467:3121–3128

    Article  PubMed  Google Scholar 

  56. Xiong Y, Yang HJ, Feng J, Shi ZL, Wu LD (2009) Effects of alendronate on the proliferation and osteogenic differentiation of MG-63 cells. J Int Med Res 37:407–416

    PubMed  CAS  Google Scholar 

  57. Pan B, To LB, Farrugia AN, Findlay DM, Green J, Gronthos S, Evdokiou A, Lynch K, Atkins GJ, Zannettino AC (2004) The nitrogen-containing bisphosphonate, zoledronic acid, increases mineralisation of human bone-derived cells in vitro. Bone 34:112–123

    Article  PubMed  CAS  Google Scholar 

  58. Idris AI, Rojas J, Greig IR, van't Hof RJ, Ralston SH (2008) Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int 82:191–201

    Article  PubMed  CAS  Google Scholar 

  59. Orriss IR, Key ML, Colston KW, Arnett TR (2009) Inhibition of osteoblast function in vitro by aminobisphosphonates. J Cell Biochem 106:109–118

    Article  PubMed  CAS  Google Scholar 

  60. Pozzi S, Vallet S, Mukherjee S, Cirstea D, Vaghela N, Santo L, Rosen E, Ikeda H, Okawa Y, Kiziltepe T, Schoonmaker J, Xie W, Hideshima T, Weller E, Bouxsein ML, Munshi NC, Anderson KC, Raje N (2009) High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. Clin Cancer Res 15:5829–5839

    Article  PubMed  CAS  Google Scholar 

  61. Greiner S, Kadow-Romacker A, Lubberstedt M, Schmidmaier G, Wildemann B (2007) The effect of zoledronic acid incorporated in a poly(D, L-lactide) implant coating on osteoblasts in vitro. J Biomed Mater Res A 80:769–775

    PubMed  CAS  Google Scholar 

  62. Kellinsalmi M, Monkkonen H, Monkkonen J, Leskela HV, Parikka V, Hamalainen M, Lehenkari P (2005) In vitro comparison of clodronate, pamidronate and zoledronic acid effects on rat osteoclasts and human stem cell-derived osteoblasts. Basic Clin Pharmacol Toxicol 97:382–391

    Article  PubMed  CAS  Google Scholar 

  63. Evans CE (2002) Bisphosphonates modulate the effect of macrophage-like cells on osteoblast. Int J Biochem Cell Biol 34:554–563

    Article  PubMed  CAS  Google Scholar 

  64. Rehinolz GG, Getz B, Pederson L et al (2000) Bisphosphonates directly regulate cell proliferation, differentiation and gene expression in human osteoblasts. Cancer Res 60:6001–6007

    Google Scholar 

  65. Giuliani N, Pedrazzoni M, Passeri G, Girasole G (1998) Bisphosphonates inhibit IL-6 production by human osteoblast-like cells. Scand J Rheumatol 27:38–41

    Article  PubMed  CAS  Google Scholar 

  66. Itoh F, Aoyagi S, Furihata-Komatsu H, Aoki M, Kusama H, Kojima M, Kogo H (2003) Clodronate stimulates osteoblast differentiation in ST2 and MC3T3-E1 cells and rat organ cultures. Eur J Pharmacol 477:9–16

    Article  PubMed  CAS  Google Scholar 

  67. D’Aoust P, McCulloch CA, Tenenbaum HC, Lekic PC (2000) Etidronate (HEBP) promotes osteoblast differentiation and wound closure in rat calvaria. Cell Tissue Res 302:353–363

    Article  PubMed  Google Scholar 

  68. Corrado A, Cantatore FP, Grano M, Colucci S (2005) Neridronate and human osteoblasts in normal, osteoporotic and osteoarthritic subjects. Clin Rheumatol 24:527–534

    Article  PubMed  Google Scholar 

  69. Corrado A, Neve A, Maruotti N, Gaudio A, Marucci A, Cantatore FP (2010) Dose-dependent metabolic effect of zoledronate on primary human osteoblastic cell cultures. Clin Exp Rheumatol 28:873–879

    PubMed  CAS  Google Scholar 

  70. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T (1999) Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104:1363–1374

    Article  PubMed  CAS  Google Scholar 

  71. Abe Y, Kawakami A, Nakashima T et al (2000) Etidronate inhibits human osteoblast apoptosis by inhibition of pro-apoptotic factor(s) produced by activated T cells. J Lab Clin Med 136:344–354

    Article  PubMed  CAS  Google Scholar 

  72. Plotkin LI, Lezcano V, Thostenson J, Weinstein RS, Manolagas SC, Bellido T (2008) Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo. J Bone Miner Res 23:1712–1721

    Article  PubMed  CAS  Google Scholar 

  73. Plotkin LI, Manolagas SC, Bellido T (2002) Transduction of cell survival signals by connexin-43 hemichannels. J Biol Chem 277:8648–8657

    Article  PubMed  CAS  Google Scholar 

  74. Kogianni G, Mann V, Ebetino F, Nuttall M, Nijweide P, Simpson H, Noble B (2004) Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis. Life Sci 75:2879–2895

    Article  PubMed  CAS  Google Scholar 

  75. Abe Y, Kawakami A, Nakashima T, Ejima E, Fujiyama K, Kiriyama T, Ide A, Sera N, Usa T, Tominaga T, Ashizawa K, Yokoyama N, Eguchi K (2000) Etidronate inhibits human osteoblast apoptosis by inhibition of pro-apoptotic factor(s) produced by activated T cells. J Lab Clin Med 136:344–354

    Article  PubMed  CAS  Google Scholar 

  76. Gangoiti MV, Cortizo AM, Arnol V, Felice JI, McCarthy AD (2008) Opposing effects of bisphosphonates and advanced glycation end-products on osteoblastic cells. Eur J Pharmacol 600:140–147

    Article  PubMed  CAS  Google Scholar 

  77. Bivi N, Bereszczak JZ, Romanello M, Zeef LA, Delneri D, Quadrifoglio F, Moro L, Brancia FL, Tell G (2009) Transcriptome and proteome analysis of osteocytes treated with nitrogen-containing bisphosphonates. J Proteome Res 8:1131–1142

    Article  PubMed  CAS  Google Scholar 

  78. Bellido T, Plotkin LI (2011) Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone 49:50–55

    Article  PubMed  CAS  Google Scholar 

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Rheumatology, University of Foggia Medical School, Foggia, Italy

    Nicola Maruotti, Addolorata Corrado, Anna Neve & Francesco Paolo Cantatore

  2. Rheumatology Clinic “Mario Carrozzo”, “D’Avanzo” Hospital, Viale degli Aviatori, 1, 71100, Foggia, Italy

    Francesco Paolo Cantatore

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  1. Nicola Maruotti
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  2. Addolorata Corrado
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  3. Anna Neve
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  4. Francesco Paolo Cantatore
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Correspondence to Francesco Paolo Cantatore.

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Maruotti, N., Corrado, A., Neve, A. et al. Bisphosphonates: effects on osteoblast. Eur J Clin Pharmacol 68, 1013–1018 (2012). https://doi.org/10.1007/s00228-012-1216-7

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  • DOI: https://doi.org/10.1007/s00228-012-1216-7

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