Iron overload in aging <em>Bmp6<sup>‑/‑</sup></em> mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss

Pauk,Martina; Kufner,Vera; Rumenovic,Viktorija; Dumic‑Cule,Ivo; Farkas,Vladimir; Milosevic,Milan; Bordukalo‑Niksic,Tatjana; Vukicevic,Slobodan

doi:10.3892/ijmm.2021.4893

April-2021 Volume 47 Issue 4

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

April-2021 Volume 47 Issue 4

Full Size Image

Article Open Access

Iron overload in aging Bmp6^‑/‑ mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss

Authors:
- Martina Pauk
- Vera Kufner
- Viktorija Rumenovic
- Ivo Dumic‑Cule
- Vladimir Farkas
- Milan Milosevic
- Tatjana Bordukalo‑Niksic
- Slobodan Vukicevic
View Affiliations / Copyright

Affiliations: Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia, Molecular Biology Department, Rudjer Boskovic Institute, HR‑10000 Zagreb, Croatia, Andrija Stampar School of Public Health, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia

Copyright: © Pauk et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 60
|
Published online on: February 19, 2021

https://doi.org/10.3892/ijmm.2021.4893
Expand metrics +

Abstract

The relationship between hemochromatosis and diabetes has been well established, as excessive iron deposition has been reported to result in impaired function of the endocrine and exocrine pancreas. Therefore, the objective of the present study was to analyze the effects of iron accumulation on the pancreata and glucose homeostasis in a bone morphogenetic protein 6‑knockout (Bmp6^‑/‑) mouse model of hemochromatosis. The sera and pancreatic tissues of wild‑type (WT) and Bmp6^‑/‑ mice (age, 3 and 10 months) were subjected to biochemical and histological analyses. In addition, ¹⁸F‑fluorodeoxyglucose biodistribution was evaluated in the liver, muscle, heart, kidney and adipose tissue of both animal groups. The results demonstrated that 3‑month‑old Bmp6^‑/‑ mice exhibited iron accumulation preferentially in the exocrine pancreas, with no signs of pancreatic injury or fibrosis. No changes were observed in the glucose metabolism, as pancreatic islet diameter, insulin and glucagon secretion, blood glucose levels and glucose uptake in the liver, muscle and adipose tissue remained comparable with those in the WT mice. Aging Bmp6^‑/‑ mice presented with progressive iron deposits in the exocrine pancreas, leading to pancreatic degeneration and injury that was characterized by acinar atrophy, fibrosis and the infiltration of inflammatory cells. However, the aging mice exhibited unaltered blood glucose levels and islet structure, normal insulin secretion and moderately increased α‑cell mass compared with those in the age‑matched WT mice. Additionally, iron overload and pancreatic damage were not observed in the aging WT mice. These results supported a pathogenic role of iron overload in aging Bmp6^‑/‑ mice leading to iron‑induced exocrine pancreatic deficiency, whereas the endocrine pancreas retained normal function.

View Figures

View References

1	Fleming RE and Ponka P: Iron overload in human disease. N Engl J Med. 366:348–359. 2012. View Article : Google Scholar : PubMed/NCBI
2	Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T and Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 306:2090–2093. 2004. View Article : Google Scholar : PubMed/NCBI
3	Pietrangelo A: Hereditary hemochromatosis: Pathogenesis, diagnosis, and treatment. Gastroenterology. 139:393–408. 408.e1–e2. 2010. View Article : Google Scholar : PubMed/NCBI
4	Piubelli C, Castagna A, Marchi G, Rizzi M, Busti F, Badar S, Marchetti M, De Gobbi M, Roetto A, Xumerle L, et al: Identification of new BMP6 pro-peptide mutations in patients with iron overload. Am J Hematol. 92:562–568. 2017. View Article : Google Scholar : PubMed/NCBI
5	Daher R, Kannengiesser C, Houamel D, Lefebvre T, Bardou-Jacquet E, Ducrot N, de Kerguenec C, Jouanolle AM, Robreau AM, Oudin C, et al: Heterozygous mutations in BmP6 pro-peptide lead to inappropriate hepcidin synthesis and moderate iron overload in humans. Gastroenterology. 150:672–683,e4. 2016. View Article : Google Scholar
6	Urist MR: Bone: Formation by autoinduction. Science. 150:893–899. 1965. View Article : Google Scholar : PubMed/NCBI
7	Reddi AH: Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol. 16:247–252. 1998. View Article : Google Scholar : PubMed/NCBI
8	Wagner Do, Sieber C, Bhushan R, Börgermann JH, Graf D and Knaus P: BMPs: From bone to body morphogenetic proteins. Sci Signal. 3:mr12010.PubMed/NCBI
9	Sampath KT: The systems biology of bone morphogenetic proteins. Bone Morphogenetic Proteins: Systems Biology Regulators. Vukicevic S and Sampath KT: Springer International Publishing; pp. 15–38. 2017
10	Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin Hy and Babitt JL: BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 41:482–487. 2009. View Article : Google Scholar : PubMed/NCBI
11	Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H and Roth MP: Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 41:478–481. 2009. View Article : Google Scholar : PubMed/NCBI
12	Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, Vukicevic S, Pietrangelo A, Lin HY and Babitt JL: BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology. 139:1721–1729. 2010. View Article : Google Scholar : PubMed/NCBI
13	Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, Lin HY, Bloch KD and Peterson RT: Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 4:33–41. 2008. View Article : Google Scholar
14	McClain DA, Abraham D, Rogers J, Brady R, Gault P, Ajioka R and Kushner JP: High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis. Diabetologia. 49:1661–1669. 2006. View Article : Google Scholar : PubMed/NCBI
15	Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, Le Gall JY, Brissot P, David V and Deugnier Y: Insulin resistance-associated hepatic iron overload. Gastroenterology. 117:1155–1163. 1999. View Article : Google Scholar : PubMed/NCBI
16	Hramiak IM, Finegood DT and Adams PC: Factors affecting glucose tolerance in hereditary hemochromatosis. Clin Invest Med. 20:110–118. 1997.PubMed/NCBI
17	Ramey G, Faye A, Durel B, Viollet B and Vaulont S: Iron overload in Hepc1(-/-) mice is not impairing glucose homeostasis. FEBS Lett. 581:1053–1057. 2007. View Article : Google Scholar : PubMed/NCBI
18	Latour C, Besson-Fournier C, Meynard D, Silvestri L, Gourbeyre O, Aguilar-Martinez P, Schmidt PJ, Fleming MD, Roth MP and Coppin H: Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin. Hepatology. 63:126–137. 2016. View Article : Google Scholar
19	Latour C, Besson-Fournier C, Gourbeyre O, Meynard D, Roth MP and Coppin H: Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge. Blood. 130:2339–2343. 2017. View Article : Google Scholar : PubMed/NCBI
20	Pauk M, Grgurevic L, Brkljacic J, Kufner V, Bordukalo-Niksic T, Grabusic K, Razdorov G, Rogic D, Zuvic M, Oppermann H, et al: Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6-/- mice. Int Orthop. 39:161–172. 2015. View Article : Google Scholar
21	Meynard D, Vaja V, Sun CC, Corradini E, Chen S, López-Otín C, Grgurevic L, Hong CC, Stirnberg M, Gütschow M, et al: Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood. 118:747–756. 2011. View Article : Google Scholar : PubMed/NCBI
22	Altamura S, Kessler R, Gröne HJ, Gretz N, Hentze MW, Galy B and Muckenthaler MU: Resistance of ferroportin to hepcidin binding causes exocrine pancreatic failure and fatal iron overload. Cell Metab. 20:359–367. 2014. View Article : Google Scholar : PubMed/NCBI
23	Lunova M, Schwarz P, Nuraldeen R, Levada K, Kuscuoglu D, Stützle M, Vujić Spasić M, Haybaeck J, Ruchala P, Jirsa M, et al: Hepcidin knockout mice spontaneously develop chronic pancreatitis owing to cytoplasmic iron overload in acinar cells. J Pathol. 241:104–114. 2017. View Article : Google Scholar
24	Cooksey RC, Jouihan HA, Ajioka Rs, Hazel MW, Jones DL, Kushner JP and McClain DA: Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. Endocrinology. 145:5305–5312. 2004. View Article : Google Scholar : PubMed/NCBI
25	Council of Europe: European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes. ETS 123; Strasbourg: 1986
26	Solloway MJ, Dudley AT, Bikoff EK, Lyons KM, Hogan BL and Robertson EJ: Mice lacking Bmp6 function. Dev Genet. 22:321–339. 1998. View Article : Google Scholar : PubMed/NCBI
27	Bhatia M, Saluja AK, Hofbauer B, Frossard JL, Lee HS, Castagliuolo I, Wang CC, Gerard N, Pothoulakis C and Steer ML: Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. Proc Natl Acad Sci uSA. 95:4760–4765. 1998. View Article : Google Scholar : PubMed/NCBI
28	Rangan GK and Tesch GH: Quantification of renal pathology by image analysis. Nephrology (Carlton). 12:553–558. 2007. View Article : Google Scholar
29	Roldan PS, Chereul E, Dietzel O, Magnier L, Pautrot C, Rbah-Vidal L, Sappey-Marinier D, Wagner A, Zimmer L, Janier MF, et al: Raytest ClearPET (TM), a new generation small animal PET scanner. Nucl Instrum Methods Phys Res A Accel Spectrom Detect Assoc Equip. 571:498–501. 2007. View Article : Google Scholar
30	Hansen JB, Moen IW and Mandrup-Poulsen T: Iron: The hard player in diabetes pathophysiology. Acta Physiol (Oxf). 210:717–732. 2014. View Article : Google Scholar
31	Buysschaert M, Paris I, Selvais P and Hermans MP: Clinical aspects of diabetes secondary to idiopathic haemochromatosis in French-speaking Belgium. Diabetes Metab. 23:308–313. 1997.PubMed/NCBI
32	Hatunic M, Finucane FM, Brennan AM, Norris S, Pacini G and Nolan JJ: Effect of iron overload on glucose metabolism in patients with hereditary hemochromatosis. Metabolism. 59:380–384. 2010. View Article : Google Scholar
33	Dichmann DS, Miller CP, Jensen J, Scott Heller R and Serup P: Expression and misexpression of members of the FGF and TGFbeta families of growth factors in the developing mouse pancreas. Dev Dyn. 226:663–674. 2003. View Article : Google Scholar : PubMed/NCBI
34	Pratt DS and Kaplan MM: Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 342:1266–1271. 2000. View Article : Google Scholar : PubMed/NCBI
35	Ramos E, Kautz L, Rodriguez R, Hansen M, Gabayan V, Ginzburg Y, Roth MP, Nemeth E and Ganz T: Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology. 53:1333–1341. 2011. View Article : Google Scholar : PubMed/NCBI
36	Canali S, Wang CY, Zumbrennen-Bullough KB, Bayer A and Babitt JL: Bone morphogenetic protein 2 controls iron homeostasis in mice independent of Bmp6. Am J Hematol. 92:1204–1213. 2017. View Article : Google Scholar : PubMed/NCBI
37	Xiao X, Dev S, Canali S, Bayer A, Xu Y, Agarwal A, Wang CY and Babitt JL: Endothelial bone morphogenetic protein 2 (Bmp2) knockout exacerbates hemochromatosis in homeostatic iron regulator (Hfe) knockout mice but not bmp6 knockout mice. Hepatology. 72:642–655. 2020. View Article : Google Scholar
38	Huang FW, Pinkus JL, Pinkus GS, Fleming MD and Andrews NC: A mouse model of juvenile hemochromatosis. J Clin Invest. 115:2187–2191. 2005. View Article : Google Scholar : PubMed/NCBI
39	Wagner J, Fillebeen C, Haliotis T, Charlebois E, Katsarou A, MUI J, Vali H and Pantopoulos K: mouse models of hereditary hemochromatosis do not develop early liver fibrosis in response to a high fat diet. PLoS one. 14:e02214552019. View Article : Google Scholar : PubMed/NCBI
40	Padda RS, Gkouvatsos K, Guido M, Mui J, Vali H and Pantopoulos K: A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv^−/− mice. Am J Physiol Gastrointest Liver Physiol. 308:G251–G261. 2015. View Article : Google Scholar
41	Mareninova OA, Sung KF, Hong P, Lugea A, Pandol SJ, Gukovsky I and Gukovskaya AS: Cell death in pancreatitis: Caspases protect from necrotizing pancreatitis. J Biol Chem. 281:3370–3381. 2006. View Article : Google Scholar
42	Pauk M, Bordukalo-Niksic T, Brkljacic J, Paralkar VM, Brault AL, Dumic-Cule I, Borovecki F, Grgurevic L and Vukicevic S: A novel role of bone morphogenetic protein 6 (BMP6) in glucose homeostasis. Acta Diabetol. 56:365–371. 2019. View Article : Google Scholar :
43	Guo Q, Wang W, Abboud R and Guo Z: Impairment of maturation of BMP-6 (35 kDa) correlates with delayed fracture healing in experimental diabetes. J Orthop Surg Res. 15:1862020. View Article : Google Scholar : PubMed/NCBI
44	Westerweel PE, van Velthoven CT, Nguyen TQ, den Ouden K, de Kleijn DP, Goumans MJ, Goldschmeding R and Verhaar MC: Modulation of TGF-β/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model. Cardiovasc Diabetol. 9:552010. View Article : Google Scholar
45	Nguyen TQ, Chon H, van Nieuwenhoven FA, Braam B, Verhaar MC and Goldschmeding R: myofibroblast progenitor cells are increased in number in patients with type 1 diabetes and express less bone morphogenetic protein 6: A novel clue to adverse tissue remodelling? Diabetologia. 49:1039–1048. 2006. View Article : Google Scholar : PubMed/NCBI
46	Vinci MC, Gambini E, Bassetti B, Genovese S and Pompilio G: When good guys turn bad: Bone marrow's and hematopoietic stem cells' role in the pathobiology of diabetic complications. Int J mol Sci. 21:38642020. View Article : Google Scholar
47	Jenkitkasemwong S, Wang CY, Coffey R, Zhang W, Chan A, Biel T, Kim JS, Hojyo S, Fukada T and Knutson MD: SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 22:138–150. 2015. View Article : Google Scholar : PubMed/NCBI
48	Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, Deng C, Vaulont S, Mosser J, Coppin H and Roth MP: Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 112:1503–1509. 2008. View Article : Google Scholar : PubMed/NCBI
49	Vujić Spasić M, Sparla R, Mleczko-Sanecka K, Migas MC, Breitkopf-Heinlein K, Dooley S, Vaulont S, Fleming RE and Muckenthaler MU: Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. Biochim Biophys Acta. 1832:76–84. 2013. View Article : Google Scholar

Journals