Vol. 2, 2017

Original research papers



N. E. Kushlinskii, E. S. Gershtein, Yu. S. Timofeev, E. A. Korotkova, I. V. Babkina, O. I. Kostyleva, Yu. N. Solovyev

Pages: 249-254

DOI: 10.21175/RadProc.2017.51

RANK/RANKL/OPG system (the key regulator of bone homeostasis) component levels were measured in blood serum of 199 patients with primary bone tumors and tumor-like lesions: 121 with bone sarcomas (53 osteosarcoma, 46 chondrosarcoma, 12 chordoma, 8 Ewing sarcoma), 32 with borderline giant cell bone tumor (GCBT), 46 with benign bone neoplasms; 131 persons comprised the control group. OPG, sRANKL, sRANK, IL-6, 8, 16 serum levels were measured by standard ELISA kits. Giant-cell bone tumor (GCBT) manifesting high osteoclastogenic and osteolytic activities was characterized by high serum content of all three components studied and the highest sRANKL/OPG ratio. The group of patients with various benign bone tumors and tumor-like lesions displayed similar to GCBT, but lower indices. Malignant bone tumor patients could be divided into 2 subgroups with opposite characteristics: osteosarcoma and Ewing sarcoma patients demonstrated low sRANK and high sRANKL levels, while chondrosarcoma and chordoma patients, on the contrary - high sRANK and low sRANKL levels. The highest IL-6 levels were revealed in GCBT patients, while serum IL-8 and IL-16 did not differ between groups. Thus, disturbances in osteolysis activators and inhibitors balance in blood serum of primary bone tumor patients were revealed. Their extent depended on neoplasm character (malignant, borderline, or benign) and histological structure of malignant sarcomas. Most prominent changes were found in GCBT characterized by active bone destruction and an accepted target of anti-RANKL antibody denosumab treatment. Hence, the proteins studied can be regarded as promising serologic markers and therapeutic targets in this rare disease.
  1. W. C. Dougall, "RANKL signaling in bone physiology and cancer," Curr. Opin. Support. Palliat. Care, vol. 1, no. 4, pp. 317-322, Dec. 2007.
    DOI: 10.1097/SPC.0b013e3282f335be
    PMid: 18685382
  2. A. Leibbrandt, J. M. Penninger, “RANKL/RANK as key factors for osteoclast development and bone loss in arthropathies,” Adv. Exp. Med. Biol., vol. 649, pp. 100-113, 2009.
    DOI: 10.1007/978-1-4419-0298-6_7
    PMid: 19731623
  3. L. Kiesel, A. Kohl, “Role of the RANK/RANKL pathway in breast cancer,” Maturitas, vol. 86, pp. 10-16, Apr. 2016.
    DOI: 10.1016/j.maturitas.2016.01.001
    PMid: 26921922
  4. A. Kukita, T. Kukita, “Multifunctional properties of RANKL/RANK in cell differentiation, proliferation and metastasis,” Future Oncol., vol. 9, no. 11, pp. 1609-1622, Nov. 2013.
    DOI: 10.2217/fon.13.115
    PMid: 24156322
  5. J. Costa-Rodrigues, C. A. Teixeira, M. H. Fernandes, “Paracrine-mediated osteoclastogenesis by the osteosarcoma MG63 cell line: is RANKL/RANK signalling really important?” Clin. Exp. Metastasis, vol. 28, no. 6, pp. 505-514, Aug. 2011.
    DOI: 10.1007/s10585-011-9387-7
    PMid: 21479680
  6. K. Mori, B. Le Goff, M. Berreur, A. Riet, A. Moreau, F. Blanchardet al., “Human osteosarcoma cells express functional receptor activator of nuclear factor-kappa B,” J. Pathol., vol. 211, no. 5, pp. 555-562, Feb. 2007.
    DOI: 10.1002/path.2140
    PMid: 17323424
  7. J. A. Lee, J. S. Jung, D. H. Kim, J. S. Lim, M. S. Kim, C. B. Konget al., “RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma,” Pediatr. Blood Cancer, vol. 56, no. 5, pp. 738-743, May 2011.
    DOI: 10.1002/pbc.22720
    PMid: 21370405
  8. Z. Wang, L. Ding, S. Zhang, T. Jiang, Y. Yang, R. Li, “Effects of icariin on the regulation of the OPG-RANKL-RANK system are mediated through the MAPK pathways in IL-1β-stimulated human SW1353 chondrosarcoma cells,” Int. J. Mol. Med., vol. 34, no. 6, pp. 1720-1726, Sep. 2014.
    DOI: 10.3892/ijmm.2014.1952
    PMid: 25270538
  9. R. Taylor, H. J. Knowles, N. A. Athanasou, “Ewing sarcoma cells express RANKL and support osteoclastogenesis,” J. Pathol., vol. 225, no. 2, pp. 195-202, Oct. 2011.
    DOI: 10.1002/path.2869
  10. D. W. Pelle, J. W. Ringler, J. D. Peacock, K. Kampfschulte, D. J. Scholten 2nd, M. M. Davis et al., “Targeting receptor-activator of nuclear kappaB ligand in aneurysmal bone cysts: verification of target and therapeutic response,” Transl. Res., vol. 164, no. 2, pp. 139-148, Aug. 2014.
    DOI: 10.1016/j.trsl.2014.03.005
    PMid: 24726460
  11. Е. С. Герштейн, Ю. С. Тимофеев, А. А. Зуев, Н. Е. Кушлинский, “Лиганд-рецепторная система RANK/RANKL/OPG и ее роль при первичных новообразованиях костей (анализ литературы и собственные результаты),” Успехи молекулярной онкологии, т. 2, no. 3, стр. 51-59, 2015. (E. S. Gershtein, Y. S. Timofeev, A. A. Zuev, N. E. Kushlinskii,”RANK/RANKL/OPG Ligand-Receptor systems and its role in primary bone neoplasms (literature analysis and own data),” Advances in molecular oncology, vol. 2, no. 3, pp. 51-59, 2015.)
    DOI: 10.17650/2313-805X.2015.2.3.51-59
  12. J. S. Burkiewicz, S. L. Scarpace, S. P. Bruce, “Denosumab in osteoporosis and oncology,” Ann. Pharmacother., vol. 43, no. 9, pp. 1445-1455, Jul. 2009.
    DOI: 10.1345/aph.1M102
    PMid: 19622756
  13. N. E. Kushlinskii, Y. S. Timofeev, Y. N. Solov’ev, E. S. Gerstein, N. V. Lyubimova, I. V. Bulycheva, “Components of the RANK/RANKL/OPG System, IL-6, IL-8, IL-16, MMP-2, and Calcitonin in the Sera of Patients with Bone Tumors,” Bulletin of Experimental Biology and Medicine, vol. 157, no. 4, pp. 520-523, Aug. 2014.
    DOI: 10.1007/s10517-014-2605-y
    PMid: 25110097
  14. D. M. Findlay, G. J. Atkins, “Relationship between serum RANKL and RANKL in bone,” Osteoporos. Int., vol. 22, no. 10, pp. 2597-2602, Oct. 2011.
    DOI: 10.1007/s00198-011-1740-9
    PMid: 21850548
  15. D. Wagner, A. Fahrleitner-Pammer, “Levels of osteoprotegerin (OPG) and receptor activator for nuclear factor kappa B ligand (RANKL) in serum: are they of any help?” Wien Med. Wochenschr., vol. 160, no. 17-18, pp. 452-457, Sep. 2010.
    DOI: 10.1007/s10354-010-0818-x
    PMid: 20714810
  16. A. S. Singh, N. S. Chawla, S. P. Chawla, “Giant-cell tumor of bone: treatment options and role of denosumab,” Biologics, vol. 9, pp. 69-74, Jul. 2015.
    DOI: 10.2147/BTT.S57359
    PMid: 26203221
    PMCid: PMC4507456
  17. A. Lopez-Pousa, J. M. Broto, T. Garrido, J. Vazquez, “Giant cell tumour of bone: new treatments in development,” Clin. Transl. Oncol., vol. 17, no. 6, pp. 419-430, Jun. 2015.
    DOI: 10.1007/s12094-014-1268-5
    PMid: 25617146
    PMCid: PMC4448077
  18. D. G. Branstetter, S. D. Nelson, J. C. Manivel, J. Y. Blay, S. Chawla, D. M. Thomas et al., “Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone,” Clin. Cancer Res., vol. 18, no. 16, pp. 4415-4424, Aug. 2012.
    DOI: 10.1158/1078-0432.CCR-12-0578
    PMid: 22711702
  19. F. C. Lam, J. E. Arle, P. A. Glazer, E. M. Kasper, “Primary Extradural Tumors of the Spine - Case Review with Evidence-guided Management,” Surg. Neurol. Int., vol. 5, no. 7, pp. S373-375, Aug. 2014.
    DOI: 10.4103/2152-7806.139673
    PMid: 25289164
    PMCid: PMC4173213
  20. R. Cathomas, C. Rothermundt, B. Bode, B. Fuchs, R. von Moos, M. Schwitter, “RANK ligand blockade with denosumab in combination with sorafenib in chemorefractory osteosarcoma: a possible step forward?” Oncology, vol. 88, no 4, pp. 257-260, Dec. 2014.
    DOI: 10.1159/000369975
    PMid: 25531914