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06 18, 2020;10 (1): 9882.

Serum hepcidin level, iron metabolism and osteoporosis in patients with rheumatoid arthritis.

Hiroe Sato, Chinatsu Takai, Junichiro James Kazama, Ayako Wakamatsu, Eriko Hasegawa, Daisuke Kobayashi, Naoki Kondo, Takeshi Nakatsue, Asami Abe, Satoshi Ito, Hajime Ishikawa, Takeshi Kuroda, Yoshiki Suzuki, Ichiei Narita
Author Information
  1. Hiroe Sato: Niigata University Health Administration Center, 2-8050 Ikarashi, Nishi-ku, Niigata City, 950-2181, Japan. hiroes@med.niigata-u.ac.jp.
  2. Chinatsu Takai: Department of Rheumatology, Niigata Rheumatic Center, 1-2-8 Honcho, Shibata City, 957-0054, Japan.
  3. Junichiro James Kazama: Department of Nephrology and Hypertension, Fukushima Medical University, 960-1295, 1 Hikariga-oka, Fukushima City, Japan.
  4. Ayako Wakamatsu: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City, 951-8510, Japan.
  5. Eriko Hasegawa: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City, 951-8510, Japan.
  6. Daisuke Kobayashi: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City, 951-8510, Japan.
  7. Naoki Kondo: Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City, 951-8510, Japan.
  8. Takeshi Nakatsue: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City, 951-8510, Japan.
  9. Asami Abe: Department of Rheumatology, Niigata Rheumatic Center, 1-2-8 Honcho, Shibata City, 957-0054, Japan.
  10. Satoshi Ito: Department of Rheumatology, Niigata Rheumatic Center, 1-2-8 Honcho, Shibata City, 957-0054, Japan.
  11. Hajime Ishikawa: Department of Rheumatology, Niigata Rheumatic Center, 1-2-8 Honcho, Shibata City, 957-0054, Japan.
  12. Takeshi Kuroda: Niigata University Health Administration Center, 2-8050 Ikarashi, Nishi-ku, Niigata City, 950-2181, Japan.
  13. Yoshiki Suzuki: Niigata University Health Administration Center, 2-8050 Ikarashi, Nishi-ku, Niigata City, 950-2181, Japan.
  14. Ichiei Narita: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City, 951-8510, Japan.
PMID: 32555299 DOI: 10.1038/s41598-020-66945-3

Abstract

Hepcidin, a major regulator of iron metabolism and homeostasis, is regulated by inflammation. Recent studies have suggested that hepcidin and iron metabolism are involved in osteoporosis, and the aim of this study was to determine whether serum hepcidin levels are correlated with the degree of osteoporosis in patients with rheumatoid arthritis (RA). A total of 262 patients with RA (67.5 ± 11.4 years; 77.5% female) were enrolled. Serum iron, ferritin, and hepcidin levels were positively correlated each other. Multiple regression analyses revealed that the serum iron level was positively correlated with femoral T and Z scores, whereas the serum hepcidin level was not. Serum hepcidin level was correlated with the serum 25-hydroxy vitamin D level, which was in turn positively related to the femoral Z score. Serum hepcidin and serum iron were indirectly and directly related to osteoporosis in patients with RA.

References

  1. Tanaka, S., Fujita, S., Kizawa, S., Morita, H. & Ishizaka, N. Association between FGF23, alpha-Klotho, and Cardiac Abnormalities among Patients with Various Chronic Kidney Disease Stages. PLoS One 11, e0156860 (2016). [PMID: 27400031]
  2. Sato, H. et al. Serum Fibroblast Growth Factor 23 (FGF23) in Patients with Rheumatoid Arthritis. Intern Med 55, 121–6 (2016). [PMID: 26781009]
  3. Wolf, M., Koch, T.A. & Bregman, D.B. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res (2013).
  4. Braithwaite, V., Prentice, A. M., Doherty, C. & Prentice, A. FGF23 is correlated with iron status but not with inflammation and decreases after iron supplementation: a supplementation study. Int J Pediatr Endocrinol 2012, 27 (2012). [PMID: 23098062]
  5. Yamazaki, M. et al. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation. J Bone Miner Metab 33, 342–54 (2015). [PMID: 24996526]
  6. Durlacher-Betzer, K. et al. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney Int 94, 315–325 (2018). [PMID: 29861060]
  7. Singh, B., Arora, S., Agrawal, P. & Gupta, S. K. Hepcidin: a novel peptide hormone regulating iron metabolism. Clin Chim Acta 412, 823–30 (2011). [PMID: 21333642]
  8. Sebastiani, G., Wilkinson, N. & Pantopoulos, K. Pharmacological Targeting of the Hepcidin/Ferroportin Axis. Front Pharmacol 7, 160 (2016). [PMID: 27445804]
  9. Chen, B., Li, G. F., Shen, Y., Huang, X. I. & Xu, Y. J. Reducing iron accumulation: A potential approach for the prevention and treatment of postmenopausal osteoporosis. Exp Ther Med 10, 7–11 (2015). [PMID: 26170904]
  10. Smith, J. T., Schneider, A. D., Katchko, K. M., Yun, C. & Hsu, E. L. Environmental Factors Impacting Bone-Relevant Chemokines. Front Endocrinol (Lausanne) 8, 22 (2017).
  11. Dede, A. D. et al. Thalassemia-associated osteoporosis: a systematic review on treatment and brief overview of the disease. Osteoporos Int 27, 3409–3425 (2016). [PMID: 27503175]
  12. Valenti, L. et al. Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int 20, 549–55 (2009). [PMID: 18661088]
  13. Kim, B. J. et al. Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: a 3-year retrospective longitudinal study. J Bone Miner Res 27, 2279–90 (2012). [PMID: 22729843]
  14. Liu, B. et al. Reduced hepcidin level features osteoporosis. Exp Ther Med 16, 1963–1967 (2018). [PMID: 30186425]
  15. Sitara, D. et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23, 421–32 (2004). [PMID: 15579309]
  16. Ostgard, R. D. et al. Hepcidin plasma levels are not associated with changes in haemoglobin in early rheumatoid arthritis patients. Scand J Rheumatol 46, 441–445 (2017). [PMID: 28482738]
  17. van Santen, S. et al. Hepcidin and hemoglobin content parameters in the diagnosis of iron deficiency in rheumatoid arthritis patients with anemia. Arthritis Rheum 63, 3672–80 (2011). [PMID: 22127690]
  18. Sahebari, M. et al. Serum hepcidin level and rheumatoid arthritis disease activity. Eur J Rheumatol 6, 76–80 (2018). [PMID: 31365340]
  19. Padjen, I. et al. Clinical meaning and implications of serum hemoglobin levels in patients with rheumatoid arthritis. Semin Arthritis Rheum 47, 193–198 (2017). [PMID: 28385457]
  20. Song, S. N. et al. Comparative evaluation of the effects of treatment with tocilizumab and TNF-alpha inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients. Arthritis Res Ther 15, R141 (2013). [PMID: 24286116]
  21. Suzuki, S. et al. Hepcidin-25 gives an indication of the therapeutic effectiveness of tocilizumab in rheumatoid arthritis - Relationship between disease activity of rheumatoid arthritis and anemia. Rev Bras Reumatol Engl Ed 57, 637–640 (2017). [PMID: 29173704]
  22. Isaacs, J. D., Harari, O., Kobold, U., Lee, J. S. & Bernasconi, C. Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis. Arthritis Res Ther 15, R204 (2013). [PMID: 24295403]
  23. Sun, L. et al. Hepcidin deficiency undermines bone load-bearing capacity through inducing iron overload. Gene 543, 161–5 (2014). [PMID: 24561287]
  24. Zhang, P. et al. Hepcidin is an endogenous protective factor for osteoporosis by reducing iron levels. J Mol Endocrinol 60, 297–306 (2018). [PMID: 29563156]
  25. Li, G. F., Pan, Y. Z., Sirois, P., Li, K. & Xu, Y. J. Iron homeostasis in osteoporosis and its clinical implications. Osteoporos Int 23, 2403–8 (2012). [PMID: 22525981]
  26. Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19, 429–35 (2004). [PMID: 15040831]
  27. Harrison, S.R., Li, D., Jeffery, L.E., Raza, K. & Hewison, M. Vitamin D, Autoimmune Disease and Rheumatoid Arthritis. Calcif Tissue Int (2019).
  28. Chen, J. et al. Vitamin D deficiency and low bone mineral density in native Chinese rheumatoid arthritis patients. Int J Rheum Dis 17, 66–70 (2014). [PMID: 24131858]
  29. Bacchetta, J. et al. Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol 25, 564–72 (2014). [PMID: 24204002]
  30. Smith, E. M. et al. High-dose vitamin D3 reduces circulating hepcidin concentrations: A pilot, randomized, double-blind, placebo-controlled trial in healthy adults. Clin Nutr 36, 980–985 (2017). [PMID: 27402475]
  31. Zughaier, S. M., Alvarez, J. A., Sloan, J. H., Konrad, R. J. & Tangpricha, V. The role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes. J Clin Transl Endocrinol 1, 19–25 (2014). [PMID: 25097830]
  32. Moran-Lev, H. et al. Vitamin D Decreases Hepcidin and Inflammatory Markers in Newly Diagnosed Inflammatory Bowel Disease Paediatric Patients: A Prospective Study. J Crohns Colitis 13, 1287–1291 (2019). [PMID: 30840757]
  33. Syed, S. et al. Vitamin D Status Is Associated with Hepcidin and Hemoglobin Concentrations in Children with Inflammatory Bowel Disease. Inflamm Bowel Dis 23, 1650–1658 (2017). [PMID: 28700535]
  34. De la Cruz-Gongora, V., Salinas-Rodriguez, A., Villalpando, S. & Flores-Aldana, M. Serum Retinol but Not 25(OH)D Status Is Associated With Serum Hepcidin Levels in Older Mexican Adults. Nutrients 11 (2019).
  35. Smith, E. M. et al. Vitamin D deficiency is associated with anaemia among African Americans in a US cohort. Br J Nutr 113, 1732–40 (2015). [PMID: 25876674]
  36. Sangkhae, V. & Nemeth, E. Regulation of the Iron Homeostatic Hormone Hepcidin. Adv Nutr 8, 126–136 (2017). [PMID: 28096133]
  37. Arnett, F. C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31, 315–24 (1988). [PMID: 3358796]
  38. Aletaha, D. et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62, 2569–81 (2010). [PMID: 20872595]
  39. Matsuo, S. et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53, 982–92 (2009). [PMID: 19339088]
  40. Payne, R. B., Little, A. J., Williams, R. B. & Milner, J. R. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 4, 643–6 (1973). [PMID: 4758544]
  41. Yamazaki, Y. et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab 87, 4957–60 (2002). [PMID: 12414858]

MeSH Term

Aged
Arthritis, Rheumatoid
Calcifediol
Female
Ferritins
Fibroblast Growth Factor-23
Fibroblast Growth Factors
Hepcidins
Humans
Inflammation
Iron
Logistic Models
Male
Middle Aged
Osteoporosis
Severity of Illness Index

Chemicals

Hepcidins
Fibroblast Growth Factors
Fibroblast Growth Factor-23
Ferritins
Iron
Calcifediol
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 7

Word Cloud

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