Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6-/- mice

International Orthopaedics

Volumn 39, Issue 1, 2015, Pages 161-172

  Pauk, Martina ^a   Grgurevic, Lovorka ^a   Brkljacic, Jelena ^a   Kufner, Vera ^a   Bordukalo Niksic, Tatjana ^a   Grabusic, Kristina ^b   Razdorov, Genadij ^a   Rogic, Dunja ^c   Zuvic, Marijan ^c   Oppermann, Hermann ^d   Babitt, Jodie L ^e   Lin, Herbert Y ^e   Volarevic, Sinisa ^b   Vukicevic, Slobodan ^a  

^a UNIVERSITY OF ZAGREB   (Croatia)

^b UNIVERSITY OF RIJEKA   (Croatia)

^c KBC Zagreb   (Croatia)

^d Genera Analytics Ltd   (Croatia)

^e HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Bone morphogenetic protein; Haemochromatosis; Hepcidin; Iron

Indexed keywords

BONE MORPHOGENETIC PROTEIN 2; BONE MORPHOGENETIC PROTEIN 4; BONE MORPHOGENETIC PROTEIN 5; BONE MORPHOGENETIC PROTEIN 6; BONE MORPHOGENETIC PROTEIN 9; HEPCIDIN; IRON; MESSENGER RNA; OSTEOGENIC PROTEIN 1; SMAD PROTEIN; TECHNETIUM 99M; BONE MORPHOGENETIC PROTEIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG DISTRIBUTION; DUODENUM; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; HEMOCHROMATOSIS; HISTOPATHOLOGY; IMMUNOHISTOCHEMISTRY; IRON OVERLOAD; ISOTOPE LABELING; LIVER; MOUSE; NONHUMAN; OSTEOPENIA; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; QUANTITATIVE ANALYSIS; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; TISSUE LEVEL; WESTERN BLOTTING; ANIMAL; BONE DISEASES, METABOLIC; GENETICS; HOMEOSTASIS; KNOCKOUT MOUSE; MALE; MASS SPECTROMETRY; METABOLISM; PHYSIOLOGY;

ANIMALS; BLOTTING, WESTERN; BONE DISEASES, METABOLIC; BONE MORPHOGENETIC PROTEINS; ENZYME-LINKED IMMUNOSORBENT ASSAY; FEMALE; HEPCIDINS; HOMEOSTASIS; IMMUNOHISTOCHEMISTRY; IRON; IRON OVERLOAD; LIVER; MALE; MASS SPECTROMETRY; MICE; MICE, KNOCKOUT; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION;

EID: 84922080278     PISSN: 03412695     EISSN: 14325195     Source Type: Journal    
DOI: 10.1007/s00264-014-2550-4     Document Type: Article

References (37)

1. Guggenbuhl P, Deugnier Y, Boisdet JF, Rolland Y, Perdriger A, Pawlotsky Y, Chalès G (2005) Bone mineral density in men with genetic hemochromatosis and HFE gene mutation. Osteoporos Int 16:1809–1814
2. 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 27:2279–22790
3. 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
4. Vukicevic S, Oppermann H, Verbanac D et al (2014) The clinical use of bone morphogenetic proteins (BMPs) revisited: A novel BMP6 biocompatible carrier device OSTEOGROW for bone healing. Int Orthop 38:635–664
5. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot B, Loréal O (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276:7811–7819
6. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Sci 306:2090–2093
7. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T (2004) IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113:1271–1276
8. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110:1037–1044
9. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY (2006) Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38:531–539
10. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY (2007) Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 117:1933–1939
11. Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700
12. Vukicevic S, Stavljenic A, Pecina M (1995) Discovery and clinical applications of bone morphogenetic proteins. Eur J Clin Chem Clin Biochem 33:661–671
13. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng CX (2005) A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2:399–409
14. Andriopoulos BJ, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL (2009) BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41:482–487
15. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP (2009) Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41:478–481
16. Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, Vukicevic S, Pietrangelo A, Lin HY, Babitt JL (2010) BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterol 139:1721–1729
17. Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, Lin HY, Bloch KD, Peterson RT (2008) Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 4:33–41
18. Truksa J, Peng H, Lee P, Beutler E (2006) Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci U S A 103:10289–10293
19. Ramos E, Kautz L, Rodriguez R, Hansen M, Gabayan V, Ginzburg Y, Roth MP, Nemeth E, Ganz T (2011) Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatol 53:1333–1341
20. Vukicevic S, Kopp JB, Luyten FP, Sampath TK (1996) Induction of nephrogenic mesenchyme by osteogenic protein 1 (bone morphogenetic protein 7). Proc Natl Acad Sci U S A 93:9021–9026
21. Vukicevic S, Grgurevic L (2009) BMP-6 and mesenchymal stem cell differentiation. Cytokine Growth Factor Rev 20:441–448
22. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, Deng C, Vaulont S, Mosser J, Coppin H, Roth MP (2008) Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112:1503–1509
23. Arndt S, Maegdefrau U, Dorn C, Schardt K, Hellerbrand C, Bosserhoff AK (2010) Iron induced expression of bone morphogenic protein 6 in intestinal cells is the main regulator of hepatic hepcidin expression in vivo. Gastroenterol 138:372–382
24. Kautz L, Besson-Fournier C, Meynard D, Latour C, Roth MP, Coppin H (2011) Iron overload induces Bmp6 expression in the liver but not in the duodenum. Haematol 96:199–203
25. Corradini E, Meynard D, Wu Q, Chen S, Ventura P, Pietrangelo A, Babitt JL (2011) Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatol 54:273–284
26. Zhang AS, Gao J, Koeberl DD, Enns CA (2010) The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo. J Biol Chem 285:16416–16423
27. Solloway MJ, Dudley AT, Bikoff EK, Lyons KM, Hogan BL, Robertson EJ (1998) Mice lacking Bmp6 function. Dev Genet 22:321–339
28. Grgurevic L, Macek B, Healy DR, Brault AL, Erjavec I, Cipcic A, Grgurevic I, Rogic D, Galesic K, Brkljacic J, Stern-Padovan R, Paralkar VM, Vukicevic S (2011) Circulating bone morphogenetic protein 1-3 isoform increases renal fibrosis. J Am Soc Nephrol 22:681–692
29. Brkljacic J, Pauk M, Erjavec I, Cipcic A, Grgurevic L, Zadro R, Inman GJ, Vukicevic S (2013) Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity. Int Orthop 37:529–541
30. Grgurevic L, Macek B, Durdevic D, Vukicevic S (2007) Detection of bone and cartilage-related proteins in plasma of patients with a bone fracture using liquid chromatography-mass spectrometry. Int Orthop 31:743–751
31. Tacke F, Gäbele E, Bataille F, Schwabe RF, Hellerbrand C, Klebl F, Straub RH, Luedde T, Manns MP, Trautwein C, Brenner DA, Schölmerich J, Schnabl B (2007) Bone morphogenetic protein 7 is elevated in patients with chronic liver disease and exerts fibrogenic effects on human hepatic stellate cells. Dig Dis Sci 52:3404–3415
32. David L, Mallet C, Keramidas M, Lamandé N, Gasc JM, Dupuis-Girod S, Plauchu H, Feige JJ, Bailly S (2008) Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res 102:914–922
33. Knittel T, Fellmer P, Müller L, Ramadori G (1997) Bone morphogenetic protein-6 is expressed in nonparenchymal liver cells and upregulated by transforming growth factor-beta 1. Exp Cell Res 232:263–269
34. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M (2008) Immunoassay for human serum hepcidin. Blood 112:4292–4297
35. Wu Q, Sun CC, Lin HY, Babitt JL (2012) Repulsive guidance molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic proteins (BMPs). PLoS One 7:e46307
36. Ozkaynak E, Schnegelsberg PN, Oppermann H (1991) Murine osteogenic protein (OP-1): high levels of mRNA in kidney. Biochem Biophys Res Commun 179:116–123
37. Theurl I, Schroll A, Nairz M, Seifert M, Theurl M, Sonnweber T, Kulaksiz H, Weiss G (2011) Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo. Haematol 96:1761–1769