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Effect of Omeprazole on Osteoblasts and Osteoclasts in vivo and in the in vitro Model Using Fish Scales

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Abstract

Omeprazole suppresses excessive secretion of gastric acid via irreversible inhibition of H+/K+-ATPase in the gastric parietal cells. Recent meta-analysis of data revealed an association between the use of proton pump inhibitors (PPIs) and increased risk of bone fractures, but the underlying molecular mechanism of PPI action remains unclear. In this study, we demonstrated that omeprazole directly influences bone metabolism using a unique in vitro bioassay system with teleost scales, as well as the in vivo model. The in vitro study showed that omeprazole significantly increased the activities of alkaline phosphatase and tartrate-resistant acid phosphatase after 6 h of incubation with this PPI. Expression of mRNAs for several osteoclastic markers was upregulated after 3-h incubation of fish scales with 10−7 M omeprazole. The in vivo experiments revealed that the plasma calcium levels significantly increased in the omeprazole-treated group. The results of in vitro and in vivo studies suggest that omeprazole affects bone cells by increasing bone resorption by upregulating expression of osteoclastic genes and promoting calcium release to the circulation. The suggested in vitro bioassay in fish scales is a practical model that can be used to study the effects of drugs on bone metabolism.

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Abbreviations

AP:

alkaline phosphatase

CTR:

calcitonin receptor

CTSK:

cathepsin K

DC-STAMP:

dendritic cell-specific transmembrane protein

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

MMP-9:

matrix metallopeptidase-9

NFATc1:

nuclear factor of activated T cells cytoplasmic 1

OPG:

osteoprotegerin

PPI:

proton pump inhibitor

RANKL:

receptor activator of nuclear factor-κB ligand

TNF:

tumor necrosis factor

TNFR:

tumor necrosis factor receptor

TRAP:

tartrate-resistant acid phosphatase

TRAF6:

TNF receptor-associated factor 6

References

  1. Kinoshita, Y., Ishimura, N., and Ishihara, S. (2018) Advantages and disadvantages of long-term proton pump inhibitor use, J. Neurogastroenterol. Motil., 24, 182-196.

    Article  Google Scholar 

  2. Tian, H., Xu, Y., Wang, J., Tian, W., Sun, J., et al. (2018) Effects of plasma albumin on the pharmacokinetics of esomeprazole in ICU patients, Biomed. Res. Int., 2018, 6374374, https://doi.org/10.1155/2018/6374374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yanagihara, G. R., de Paiva, A. G., Neto, M. P., Torres, L. H., Shimano, A. C., et al. (2015) Effects of long-term administration of omeprazole on bone mineral density and the mechanical properties of the bone, Rev. Bras. Ortop., 50, 232-238.

    Article  Google Scholar 

  4. Thaler, H. W., Sterke, C. S., and Van Der Cammen, T. J. M. (2016) Association of proton pump inhibitor use with recurrent falls and risk of fractures in older women: a study of medication use in older fallers, J. Nutr. Health Aging, 20, 77-81.

    Article  CAS  Google Scholar 

  5. Thong, B. K. S., Ima-Nirwana, S., and Chin, K. Y. (2019) Proton pump inhibitors and fracture risk: A review of current evidence and mechanisms involved, Int. J. Environ. Res. Public Health, 16, 1571.

    Article  CAS  Google Scholar 

  6. FDA Drug Safety Communication (2011) Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors, Update: 3/23/2011. Avilable at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-possible-increased-risk-fractures-hip-wrist-and-spine-use-proton-pump.

  7. Andersen, T. L., Sondergaard, T. E., Skorzynska, K. E., Dagnaes-Hansen, F., Plesner, T. L., et al. (2009) A physical mechanism for coupling bone resorption and formation in adult human bone, Am. J. Pathol., 174, 239-247.

    Article  CAS  Google Scholar 

  8. Florencio-Silva, R., Sasso, G. R., Sasso-Cerri, E., Simões, M. J., and Cerri, P. S. (2015) Biology of bone tissue: structure, function, and factors that influence bone cells, Biomed Res. Int., 2015, 421746, https://doi.org/10.1155/2015/421746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zohar, R. (2012) Signals between cells and matrix mediate bone regeneration, in: Bone Regeneration, Haim Tal, IntechOpen, https://doi.org/10.5772/38292.

  10. Manolagas, S. C. (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis, Endocr. Rev., 21, 115-137.

    CAS  PubMed  Google Scholar 

  11. Suzuki, N., Suzuki, T., and Kurokawa, T. (2000) Suppression of osteoclastic activities by calcitonin in the scales of goldfish (freshwater teleost) and nibbler fish (seawater teleost), Peptides, 21, 115-124.

    Article  CAS  Google Scholar 

  12. Thamamongood, T. A., Furuya, R., Fukuba, S., Nakamura, M., Suzuki, N., and Hattori, A. (2012) Expression of osteoblastic and osteoclastic genes during spontaneous regeneration and autotransplantation of goldfish scale: a new tool to study intramembranous bone regeneration, Bone, 50, 1240-1249.

    Article  CAS  Google Scholar 

  13. Briganti, S. I., Naciu, A. M., Tabacco, G., Cesareo, R., Napoli, N., et al. (2021) Proton Pump Inhibitors and Fractures in Adults: A Critical Appraisal and Review of the Literature, Int. J. Endocrinol., https://doi.org/10.1155/2021/8902367.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Suzuki, N., Kitamura, K., Nemoto, T., Shimizu, N., Wada, S., et al. (2007) Effect of vibration on osteoblastic and osteoclastic activities: Analysis of bone metabolism using goldfish scale as a model for bone, Adv. Sp. Res., 40, 1711-1721.

    Article  CAS  Google Scholar 

  15. Al Subaie, A., Emami, E., Tamimi, I., Laurenti, M., Eimar, H., et al (2016) Systemic administration of omeprazole interferes with bone healing and implant osseointegration: an in vivo study on rat tibiae, J. Clin. Periodontol., 43, 193-203.

    Article  CAS  Google Scholar 

  16. Wang, L., Li, M., Cao, Y., Han, Z., Wang, X., et al. (2017) Proton pump inhibitors and the risk for fracture at specific sites: data mining of the FDA adverse event reporting system, Sci. Rep., 7, 5527.

    Article  Google Scholar 

  17. Prause, M., Seeliger, C., Unger, M., van Griensven, M., and Haug, A. T. (2014) Pantoprazole increases cell viability and function of primary human osteoblasts in vitro, Injury, 45, 1156-1164.

    Article  Google Scholar 

  18. Prause, M., Seeliger, C., Unger, M., Rosado Balmayor, E., van Griensven, M., and Haug, A. T. (2015) Pantoprazole decreases cell viability and function of human osteoclasts in vitro, Mediators Inflamm., 2015, 413097, https://doi.org/10.1155/2015/413097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shetty, S., Kapoor, N., Bondu, J. D., Thomas, N., and Paul, T. V. (2016) Bone turnover markers: Emerging tool in the management of osteoporosis, Ind. J. Endocrinol. Metab., 20, 846-852.

    Article  Google Scholar 

  20. Costa-Rodrigues, J., Reis, S., Teixeira, S., Lopes, S., and Fernandes, M. H. (2013) Dose-dependent inhibitory effects of proton pump inhibitors on human osteoclastic and osteoblastic cell activity, FEBS J., 280, 5052-5064.

    Article  CAS  Google Scholar 

  21. Hyun, J. J., Chun, H. J., Keum, B., Seo, Y. S., Kim, Y. S., et al. (2010) Effect of omeprazole on the expression of transcription factors in osteoclasts and osteoblasts, Int. J. Mol. Med., 26, 877-883.

    CAS  PubMed  Google Scholar 

  22. Robling, A. G., Castillo, A. B., and Turner, C. H. (2006) Biomechanical and molecular regulation of bone remodeling, Annu. Rev. Biomed. Eng., 8, 455-498.

    Article  CAS  Google Scholar 

  23. Price, C. T., Langford, J. R., and Liporace, F. A. (2012) Essential nutrients for bone health and a review of their availability in the average North American Diet, Open Orthop. J., 6, 143-149.

    Article  Google Scholar 

  24. Minisola, S., Pepe, J., Piemonte, S., and Cipriani, C. (2015) The diagnosis and management of hypercalcaemia, BMJ, 350, h2723, https://doi.org/10.1136/bmj.h2723.

    Article  CAS  PubMed  Google Scholar 

  25. Ye, X., Liu, H., Wu, C., Qin, Y., Zang, J., et al. (2011) Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis, Eur. J. Gastroenterol. Hepatol., 23, 794-800.

    Article  CAS  Google Scholar 

  26. O’Connell, M. B., Madden, D. M., Murray, A. M., Heaney, R. P., and Kerzner, L. J. (2005) Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial, Am. J. Med., 118, 778-781.

    Article  Google Scholar 

  27. Wu, X., Al-Abedalla, K., Abi-Nader, S., Daniel, N. G., Nicolau, B., and Tamimi, F. (2017) Proton pump inhibitors and the risk of osseointegrated dental implant failure: a cohort study, Clin. Implant. Dent. Relat. Res., 19, 222-232.

    Article  Google Scholar 

  28. Goltzman, D., Mannstadt, M., and Marcocci, C. (2018) Physiology of the calcium-parathyroid hormone-vitamin D axis, Front. Horm. Res., 50, 1-13.

    Article  CAS  Google Scholar 

  29. Moe, S. M. (2008) Disorders involving calcium, phosphorus, and magnesium, Primary Care, 35, 215-237.

    Article  Google Scholar 

  30. Suzuki, N., Kitamura, K., and Hattori, A. (2016) Fish scale is a suitable model for analyzing determinants of skeletal fragility in type 2 diabetes, Endocrine, 54, 575-577.

    Article  CAS  Google Scholar 

  31. Suzuki, N., Danks, J. A., Maruyama, Y., Ikegame, M., Sasayama, Y., et al. (2011) Parathyroid hormone 1 (1-34) acts on the scales and involves calcium metabolism in goldfish, Bone, 48, 1186-1193.

    Article  CAS  Google Scholar 

  32. Romdhane, H., Ayadi, S., Elleuch, N., and Abdelghani, K. (2018) Effect of long-term proton pump inhibitors on bone mineral density, Tunis Med., 96, 193-197.

    PubMed  Google Scholar 

  33. Corley, D. A., Kubo, A., Zhao, W., and Quesenberry, C. (2010) Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients, Gastroenterology, 139, 93-101.

    Article  Google Scholar 

  34. Nassar, Y., and Richter, S. (2018) Proton-pump inhibitor use and fracture risk: an updated systematic review and meta-analysis, J. Bone Metab., 25, 141-151.

    Article  Google Scholar 

  35. Sims, N. A., and Martin, T. J. (2014) Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit, Bonekey Rep., 3, 481.

    PubMed  PubMed Central  Google Scholar 

  36. Park, J. H., Lee, N. K., and Lee, S. Y. (2017) Current understanding of RANK signaling in osteoclast differentiation and maturation, Mol. Cells, 40, 706-713.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lacey, D. L., Boyle, W. J., Simonet, W. S., Kostenuik, P. J., Dougall, W. C., et al. (2012) Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab, Nat. Rev. Drug Discov., 11, 401-419.

    Article  CAS  Google Scholar 

  38. Liu, W., and Zhang, X. (2015) Receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin system in bone and other tissues (review), Mol. Med. Rep., 11, 3212-3218.

    Article  CAS  Google Scholar 

  39. Walsh, M. C., Lee, J., and Choi, Y. (2015) Tumor necrosis factor receptor-associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system, Immunol. Rev., 266, 72-92.

    Article  CAS  Google Scholar 

  40. Kobayashi, Y., Udagawa, N., and Takahashi, N. (2009) Action of RANKL and OPG for osteoclastogenesis, Crit. Rev. Eukaryot. Gene Expr., 19, 61-72.

    Article  CAS  Google Scholar 

  41. Asagiri, M., and Takayanagi, H. (2007) The molecular understanding of osteoclast differentiation, Bone, 40, 251-264.

    Article  CAS  Google Scholar 

  42. Takayanagi, H., Kim, S., Koga, T., Nishina, H., Isshiki, M.,et al. (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts, Dev. Cell, 3, 889-901.

    Article  CAS  Google Scholar 

  43. Lee, J. U., Kim, L. K., and Choi, J. M. (2018) Revisiting the concept of targeting NFAT to control T cell immunity and autoimmune diseases, Front. Immunol., 9, 2747.

    Article  Google Scholar 

  44. Hutchings, G., Moncrieff, L., Dompe, C., Janowicz, K., Sibiak, R., et al. (2020) Bone regeneration, reconstruction and use of osteogenic cells; from basic knowledge, animal models to clinical trials, J. Clin. Med., 9, 139, https://doi.org/10.3390/jcm9010139.

    Article  CAS  PubMed Central  Google Scholar 

  45. Podgorski, I., Linebaugh, B. E., Koblinski, J. E., Rudy, D. L., Herroon, M. K., et al. (2009) Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis, Am. J. Pathol., 175, 1255-1269.

    Article  CAS  Google Scholar 

  46. Chiu, Y. H., and Ritchlin, C. T. (2016) DC-STAMP: a key regulator in osteoclast differentiation, J. Cell Physiol., 231, 2402-2407.

    Article  CAS  Google Scholar 

  47. Herroon, M. K., Rajagurubandara, E., Rudy, D. L., Chalasani, A., Hardaway, A. L., and Podgorski, I. (2013) Macrophage cathepsin K promotes prostate tumor progression in bone, Oncogene, 32, 1580-1593.

    Article  CAS  Google Scholar 

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Acknowledgments

We are grateful to all staff members of the Noto Marine Laboratory, Division of Marine Environmental Studies, Institute of Nature and Environmental Technology, Kanazawa University, Noto-Cho, Ishikawa, Japan, for their endless support during the experimental study.

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Authors and Affiliations

  1. Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, 62511, Beni-Suef, Egypt

    Mohamed I. Zanaty

  2. Molecular Physiology Division, Faculty of Science, Beni-Suef University, 62511, Beni-Suef, Egypt

    Adel Abdel-Moneim

  3. Noto Marine Laboratory, Division of Marine Environmental Studies, Institute of Nature and Environmental Technology, Kanazawa University, 927-0553, Noto-Cho, Ishikawa, Japan

    Yoichiro Kitani, Toshio Sekiguchi & Nobuo Suzuki

Authors
  1. Mohamed I. Zanaty
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  2. Adel Abdel-Moneim
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  5. Nobuo Suzuki
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Correspondence to Adel Abdel-Moneim.

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The authors declare no conflict of interest. The experiment was performed in agreement with the guidelines for the care and use of laboratory animals of the Kanazawa University (Protocol No. 93255).

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Zanaty, M.I., Abdel-Moneim, A., Kitani, Y. et al. Effect of Omeprazole on Osteoblasts and Osteoclasts in vivo and in the in vitro Model Using Fish Scales. Biochemistry Moscow 86, 1192–1200 (2021). https://doi.org/10.1134/S0006297921100035

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  • DOI: https://doi.org/10.1134/S0006297921100035

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