Biological Trace Element Research

, Volume 187, Issue 2, pp 434–441 | Cite as

Iron Accumulation Leads to Bone Loss by Inducing Mesenchymal Stem Cell Apoptosis Through the Activation of Caspase3

  • Ye Yuan
  • Fei Xu
  • Yan Cao
  • Li Xu
  • Chen Yu
  • Fan Yang
  • Peng Zhang
  • Liang Wang
  • Guangsi Shen
  • Jianrong Wang
  • Youjia XuEmail author


Osteoporosis (OP) is a disease associated with bone loss and microstructure degradation. Recent studies have shown that iron accumulation may be a risk factor for OP. Bone marrow mesenchymal stem cells (MSCs) are multipotent cells and precursors to osteoblasts. MSCs play an important role in OP. Therefore, we evaluated the correlation between MSCs and OP in an environment of iron accumulation. Serum P1NP was decreased in iron accumulation mice. Micro-CT revealed that iron accumulation decreased bone mineral density and spatial structural parameters. Iron accumulation inhibited MSC quantity in bone marrow. However, the iron chelator deferoxamine (DFO) rescued the suppression. Iron accumulation also changed the MSC cell cycle. Iron elevated MSC cell ROS level and NOX4 protein expression. MSC apoptosis was increased, and more caspase3 was cleaved after iron intervention. Our data suggests that iron accumulation inhibits MSC quantity and induces MSC apoptosis. Bone loss from iron accumulation may correlate with the inhibition of MSCs.


Iron accumulation Bone loss Bone marrow mesenchymal stem cells 


Funding Information

This work was supported by grants from the Natural Science Foundation of China (81572179 and 81773439), the Clinical Medicine Technology Project of Jiangsu Province (BL2014044), the Minsheng Science and Technology Project of Suzhou City (SS201634), Clinical Medical Center Project of Suzhou City (SZZX201504), Advantage Discipline Groups of the Second Affiliated Hospital of Soochow University (XKQ2015001), the Second Affiliate Hospital of Soochow University Pre-research Foundation (SDFEYQN1608), Jiangsu Province’s Young Medical Talents Program (QNRC2016880), and Soochow University Youth Teacher Science Fund Project (SDY2011A28).


  1. 1.
    Moriwaki S, Suzuki K, Muramatsu M, Nomura A, Inoue F, Into T, Yoshiko Y, Niida S (2014) Delphinidin, one of the major anthocyanidins, prevents bone loss through the inhibition of excessive osteoclastogenesis in osteoporosis model mice. PLoS One 9:e97177. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Weinberg ED (2006) Iron loading: a risk factor for osteoporosis. Biometals 19:633–635. CrossRefPubMedGoogle Scholar
  3. 3.
    Valenti L, Varenna M, Fracanzani AL, Rossi V, Fargion S, Sinigaglia L (2009) Association between iron overload and osteoporosis in patients with hereditary hemochromatosis. Osteoporos Int 20:549–555. CrossRefPubMedGoogle Scholar
  4. 4.
    Rossi F, Perrotta S, Bellini G, Luongo L, Tortora C, Siniscalco D, Francese M, Torella M, Nobili B, Di Marzo V, Maione S (2014) Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels. Haematologica 99:1876–1884. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY (2013) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 24:23–57. CrossRefPubMedGoogle Scholar
  6. 6.
    Kim BJ, Ahn SH, Bae SJ, Kim EH, Lee SH, Kim HK, Choe JW, Koh JM, Kim GS (2012) Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: a 3-year retrospective longitudinal study. J Bone Miner Res 27:2279–2290. CrossRefPubMedGoogle Scholar
  7. 7.
    Jian J, Pelle E, Huang X (2009) Iron and menopause: does increased iron affect the health of postmenopausal women? Antioxid Redox Signal 11:2939–2943. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Huang X, Xu Y, Partridge NC (2013) Dancing with sex hormones, could iron contribute to the gender difference in osteoporosis? Bone 55:458–460. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Li GF, Pan YZ, Sirois P, Li K, Xu YJ (2012) Iron homeostasis in osteoporosis and its clinical implications. Osteoporos Int 23:2403–2408. CrossRefPubMedGoogle Scholar
  10. 10.
    Weinberg ED (2008) Role of iron in osteoporosis. Pediatr Endocrinol Rev 6(Suppl 1):81–85. CrossRefPubMedGoogle Scholar
  11. 11.
    Tsay J, Yang Z, Ross FP, Cunningham-Rundles S, Lin H, Coleman R, Mayer-Kuckuk P, Doty SB, Grady RW, Giardina PJ, Boskey AL, Vogiatzi MG (2010) Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood 116:2582–2589. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zarjou A, Jeney V, Arosio P, Poli M, Zavaczki E, Balla G, Balla J (2010) Ferritin ferroxidase activity: a potent inhibitor of osteogenesis. J Bone Miner Res 25:164–172. CrossRefPubMedGoogle Scholar
  13. 13.
    Jackson WM, Nesti LJ, Tuan RS (2012) Concise review: clinical translation of wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med 1:44–50. CrossRefPubMedGoogle Scholar
  14. 14.
    Chamberlain G, Fox J, Ashton B, Middleton J (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25:2739–2749. CrossRefPubMedGoogle Scholar
  15. 15.
    Lu WY, Zhao MF, Chai X, Meng JX, Zhao N, Rajbhandary S, Xu XN, Ma L, Li YM (2013) Reactive oxygen species mediate the injury and deficient hematopoietic supportive capacity of umbilical cord derived mesenchymal stem cells induced by iron overload. Zhonghua Yi Xue Za Zhi 93:930–934PubMedGoogle Scholar
  16. 16.
    Lu WY, Zhao MF, Sajin R, Zhao N, Xie F, Xiao X, Mu J, Li YM (2013) Effect and mechanism of iron-catalyzed oxidative stress on mesenchymal stem cells. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 35:6–12. CrossRefPubMedGoogle Scholar
  17. 17.
    Lu W, Zhao M, Rajbhandary S, Xie F, Chai X, Mu J, Meng J, Liu Y, Jiang Y, Xu X, Meng A (2013) Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cells in vitro and suppresses hematopoiesis in iron overload patients. Eur J Haematol 91:249–261. CrossRefPubMedGoogle Scholar
  18. 18.
    Lu H, Lian L, Shi D, Zhao H, Dai Y (2015) Hepcidin promotes osteogenic differentiation through the bone morphogenetic protein 2/small mothers against decapentaplegic and mitogen-activated protein kinase/P38 signaling pathways in mesenchymal stem cells. Mol Med Rep 11:143–150. CrossRefPubMedGoogle Scholar
  19. 19.
    Link G, Ponka P, Konijn AM, Breuer W, Cabantchik ZI, Hershko C (2003) Effects of combined chelation treatment with pyridoxal isonicotinoyl hydrazone analogs and deferoxamine in hypertransfused rats and in iron-loaded rat heart cells. Blood 101:4172–4179. CrossRefPubMedGoogle Scholar
  20. 20.
    Wang L, Zhou F, Zhang P, Wang H, Qu Z, Jia P, Yao Z, Shen G, Li G, Zhao G, Li J, Mao Y, Xie Z, Xu W, Xu Y, Xu Y (2017) Human type H vessels are a sensitive biomarker of bone mass. Cell Death Dis 8:e2760. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wang L, Jia P, Shan Y, Hao Y, Wang X, Jiang Y, Yuan Y, Du Q, Zhang H, Yang F, Zhang W, Sheng M, Xu Y (2017) Synergistic protection of bone vasculature and bone mass by desferrioxamine in osteoporotic mice. Mol Med Rep 16:6642–6649. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Morikawa S, Mabuchi Y, Kubota Y, Nagai Y, Niibe K, Hiratsu E, Suzuki S, Miyauchi-Hara C, Nagoshi N, Sunabori T, Shimmura S, Miyawaki A, Nakagawa T, Suda T, Okano H, Matsuzaki Y (2009) Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med 206:2483–2496. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Xiao W, Beibei F, Guangsi S, Yu J, Wen Z, Xi H, Youjia X (2015) Iron overload increases osteoclastogenesis and aggravates the effects of ovariectomy on bone mass. J Endocrinol 226:121–134. CrossRefPubMedGoogle Scholar
  24. 24.
    Zhao GY, Zhao LP, He YF, Li GF, Gao C, Li K, Xu YJ (2012) A comparison of the biological activities of human osteoblast hFOB1.19 between iron excess and iron deficiency. Biol Trace Elem Res 150:487–495. CrossRefPubMedGoogle Scholar
  25. 25.
    Cao Y, Zhang A, Cai J, Yuan N, Lin W, Liu S, Xu F, Song L, Li X, Fang Y, Wang Z, Wang Z, Wang J, Zhang H, Zhao W, Hu S, Zhang S, Wang J (2015) Autophagy regulates the cell cycle of murine HSPCs in a nutrient-dependent manner. Exp Hematol 43:229–242. CrossRefPubMedGoogle Scholar
  26. 26.
    Cao Y, Fang Y, Cai J, Li X, Xu F, Yuan N, Zhang S, Wang J (2016) ROS functions as an upstream trigger for autophagy to drive hematopoietic stem cell differentiation. Hematology 21:613–618. CrossRefPubMedGoogle Scholar
  27. 27.
    Yuan N, Song L, Zhang S, Lin W, Cao Y, Xu F, Fang Y, Wang Z, Zhang H, Li X, Wang Z, Cai J, Wang J, Zhang Y, Mao X, Zhao W, Hu S, Chen S, Wang J (2015) Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia. Haematologica 100:345–356. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Shen GS, Yang Q, Jian JL, Zhao GY, Liu LL, Wang X, Zhang W, Huang X, Xu YJ (2014) Hepcidin1 knockout mice display defects in bone microarchitecture and changes of bone formation markers. Calcif Tissue Int 94:632–639. CrossRefPubMedGoogle Scholar
  29. 29.
    Jia P, Xu YJ, Zhang ZL, Li K, Li B, Zhang W, Yang H (2012) Ferric ion could facilitate osteoclast differentiation and bone resorption through the production of reactive oxygen species. J Orthop Res 30:1843–1852. CrossRefPubMedGoogle Scholar
  30. 30.
    Neve A, Corrado A, Cantatore FP (2011) Osteoblast physiology in normal and pathological conditions. Cell Tissue Res 343:289–302. CrossRefPubMedGoogle Scholar
  31. 31.
    Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247. CrossRefPubMedGoogle Scholar
  32. 32.
    He YF, Ma Y, Gao C, Zhao GY, Zhang LL, Li GF, Pan YZ, Li K, Xu YJ (2013) Iron overload inhibits osteoblast biological activity through oxidative stress. Biol Trace Elem Res 152:292–296. CrossRefPubMedGoogle Scholar
  33. 33.
    Hinoi E, Fujimori S, Wang L, Hojo H, Uno K, Yoneda Y (2006) Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation. J Biol Chem 281:18015–18024. CrossRefPubMedGoogle Scholar
  34. 34.
    Bai XC, Lu D, Bai J, Zheng H, Ke ZY, Li XM, Luo SQ (2004) Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 314:197–207CrossRefGoogle Scholar
  35. 35.
    Almeida M, Han L, Martin-Millan M, O'Brien CA, Manolagas SC (2007) Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J Biol Chem 282:27298–27305. CrossRefPubMedGoogle Scholar
  36. 36.
    Atashi F, Modarressi A, Pepper MS (2015) The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: a review. Stem Cells Dev 24:1150–1163. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Goettsch C, Babelova A, Trummer O, Erben RG, Rauner M, Rammelt S, Weissmann N, Weinberger V, Benkhoff S, Kampschulte M, Obermayer-Piesch B, Hofbauer LC, Brandes RP, SchroderK (2013) NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis. J Clin Invest 123:4731–4738. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Schroder K, Wandzioch K, Helmcke I, Brandes RP (2009) Nox4 acts as a switch between differentiation and proliferation in preadipocytes. Arterioscler Thromb Vasc Biol 29:239–245. CrossRefPubMedGoogle Scholar
  39. 39.
    Kanda Y, Hinata T, Kang SW, Watanabe Y (2011) Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. Life Sci 89:250–258. CrossRefPubMedGoogle Scholar
  40. 40.
    Mouche S, Mkaddem SB, Wang W, Katic M, Tseng YH, Carnesecchi S, Steger K, Foti M, Meier CA, Muzzin P, Kahn CR, Ogier-Denis E, Szanto I (2007) Reduced expression of the NADPH oxidase NOX4 is a hallmark of adipocyte differentiation. Biochim Biophys Acta 1773:1015–1027. CrossRefPubMedGoogle Scholar
  41. 41.
    Della-Fera MA, Li C, Baile CA (2003) Resistance to IP leptin-induced adipose apoptosis caused by high-fat diet in mice. Biochem Biophys Res Commun 303:1053–1057CrossRefGoogle Scholar
  42. 42.
    Rahmani M, Davis EM, Bauer C, Dent P, Grant S (2005) Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem 280:35217–35227. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Salvesen GS (2002) Caspases: opening the boxes and interpreting the arrows. Cell Death Differ 9:3–5. CrossRefPubMedGoogle Scholar
  44. 44.
    Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, Halayko AJ, Los M (2009) Apoptosis and cancer: mutations within caspase genes. J Med Genet 46:497–510. CrossRefPubMedGoogle Scholar
  45. 45.
    Walters J, Pop C, Scott FL, Drag M, Swartz P, Mattos C, Salvesen GS, Clark AC (2009) A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis. Biochem J 424:335–345. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ye Yuan
    • 1
  • Fei Xu
    • 2
    • 3
  • Yan Cao
    • 2
  • Li Xu
    • 2
  • Chen Yu
    • 1
  • Fan Yang
    • 4
  • Peng Zhang
    • 1
  • Liang Wang
    • 1
  • Guangsi Shen
    • 1
  • Jianrong Wang
    • 2
  • Youjia Xu
    • 1
    • 4
    Email author
  1. 1.Department of OrthopedicsThe Second Affiliated Hospital of Soochow UniversitySuzhouChina
  2. 2.Hematology Center of Cyrus Tang Medical InstituteSoochow University School of MedicineSuzhouChina
  3. 3.Department of Basic Medicine, Wuxi School of MedicineJiangnan UniversityWuxiChina
  4. 4.Osteoporosis Institute of Soochow UniversitySuzhouChina

Personalised recommendations