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

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.

[1]  Jodie L Babitt,et al.  Endothelial Bone Morphogenetic Protein 2 (Bmp2) Knockout Exacerbates Hemochromatosis in Homeostatic Iron Regulator (Hfe) Knockout Mice but not Bmp6 Knockout Mice , 2020 .

[2]  S. Genovese,et al.  When Good Guys Turn Bad: Bone Marrow’s and Hematopoietic Stem Cells’ Role in the Pathobiology of Diabetic Complications , 2020, International journal of molecular sciences.

[3]  R. Abboud,et al.  Impairment of maturation of BMP-6 (35 kDa) correlates with delayed fracture healing in experimental diabetes , 2020, Journal of Orthopaedic Surgery and Research.

[4]  S. Vukicevic,et al.  A novel role of bone morphogenetic protein 6 (BMP6) in glucose homeostasis , 2018, Acta Diabetologica.

[5]  H. Vali,et al.  Mouse models of hereditary hemochromatosis do not develop early liver fibrosis in response to a high fat diet , 2018, bioRxiv.

[6]  M. Roth,et al.  Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge. , 2017, Blood.

[7]  Jodie L Babitt,et al.  Bone morphogenetic protein 2 controls iron homeostasis in mice independent of Bmp6 , 2017, American journal of hematology.

[8]  D. Girelli,et al.  Identification of new BMP6 pro‐peptide mutations in patients with iron overload , 2017, American journal of hematology.

[9]  C. Trautwein,et al.  Hepcidin knockout mice spontaneously develop chronic pancreatitis owing to cytoplasmic iron overload in acinar cells , 2017, The Journal of pathology.

[10]  C. Beaumont,et al.  Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans. , 2016, Gastroenterology.

[11]  L. Silvestri,et al.  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 , 2016, Hepatology.

[12]  Wei Zhang,et al.  SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis. , 2015, Cell metabolism.

[13]  H. Vali,et al.  A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv⁻/⁻ mice. , 2015, American Journal of Physiology - Gastrointestinal and Liver Physiology.

[14]  M. Hentze,et al.  Resistance of ferroportin to hepcidin binding causes exocrine pancreatic failure and fatal iron overload. , 2014, Cell metabolism.

[15]  J. Hansen,et al.  Iron: the hard player in diabetes pathophysiology , 2014, Acta physiologica.

[16]  P. Ponka,et al.  Iron overload in human disease. , 2012, The New England journal of medicine.

[17]  T. Ganz,et al.  Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice , 2011, Hepatology.

[18]  S. Vukicevic,et al.  BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. , 2010, Gastroenterology.

[19]  M. Goumans,et al.  Modulation of TGF-β/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model , 2010, Cardiovascular diabetology.

[20]  A. Pietrangelo.  Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. , 2010, Gastroenterology.

[21]  G. Pacini,et al.  Effect of iron overload on glucose metabolism in patients with hereditary hemochromatosis. , 2010, Metabolism: clinical and experimental.

[22]  P. Knaus,et al.  BMPs: From Bone to Body Morphogenetic Proteins , 2010, Science Signaling.

[23]  M. Roth,et al.  Lack of the bone morphogenetic protein BMP6 induces massive iron overload , 2009, Nature Genetics.

[24]  Yin Xia,et al.  BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism , 2009, Nature Genetics.

[25]  Jean Mosser,et al.  Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. , 2008, Blood.

[26]  B. Viollet,et al.  Iron overload in Hepc1 −/− mice is not impairing glucose homeostasis , 2007, FEBS letters.

[27]  Dominique Sappey-Marinier,et al.  Raytest ClearPET™, a new generation small animal PET scanner , 2007 .

[28]  R. Goldschmeding,et al.  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? , 2006, Diabetologia.

[29]  D. McClain,et al.  High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis , 2006, Diabetologia.

[30]  G. Pinkus,et al.  A mouse model of juvenile hemochromatosis. , 2005, The Journal of clinical investigation.

[31]  Jerry Kaplan,et al.  Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization , 2004, Science.

[32]  R. Cooksey,et al.  Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. , 2004, Endocrinology.

[33]  P. Serup,et al.  Expression and misexpression of members of the FGF and TGFβ families of growth factors in the developing mouse pancreas , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[34]  M. Kaplan,et al.  Evaluation of abnormal liver-enzyme results in asymptomatic patients. , 2000, The New England journal of medicine.

[35]  J. L. Le Gall,et al.  Insulin resistance-associated hepatic iron overload. , 1999, Gastroenterology.

[36]  C. Pothoulakis,et al.  Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[37]  A. Reddi,et al.  Role of morphogenetic proteins in skeletal tissue engineering and regeneration , 1998, Nature Biotechnology.

[38]  M. Hermans,et al.  Clinical aspects of diabetes secondary to idiopathic haemochromatosis in French-speaking Belgium. , 1997, Diabetes & metabolism.

[39]  M. Urist,et al.  Bone: Formation by Autoinduction , 1965, Science.

[40]  K. Sampath.  The Systems Biology of Bone Morphogenetic Proteins , 2017 .

[41]  S. Vukicevic,et al.  Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6-/- mice , 2014, International Orthopaedics.

[42]  S. Dooley,et al.  Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. , 2013, Biochimica et biophysica acta.

[43]  Charles C Hong,et al.  Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. , 2008, Nature chemical biology.

[44]  G. Rangan,et al.  Quantification of renal pathology by image analysis. , 2007, Nephrology.

[45]  B. Hogan,et al.  Mice lacking Bmp6 function. , 1998, Developmental genetics.

[46]  I. Hramiak,et al.  Factors affecting glucose tolerance in hereditary hemochromatosis. , 1997, Clinical and investigative medicine. Medecine clinique et experimentale.