title: Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6-/- mice.
abstract: OBJECTIVE
  Iron overload accelerates bone loss in mice lacking the bone morphogenetic protein 6 (Bmp6) gene, which is the key endogenous regulator of hepcidin, iron homeostasis gene. We investigated involvement of other BMPs in preventing haemochromatosis and subsequent osteopenia in Bmp6-/- mice.
  
  
  METHODS
  Iron-treated wild-type (WT) and Bmp6-/- mice were analysed for hepcidin messenger RNA (mRNA) and tissue and blood BMP levels by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), immunohistochemistry, Western blot, enzyme-linked immunosorbent assay (ELISA) and proximity extension assay. BMPs labeled with technetium-99m were used in pharmacokinetic studies.
  
  
  RESULTS
  In WT mice, 4 h following iron challenge, liver Bmp6 and hepcidin expression were increased, while expression of other Bmps was not affected. In parallel, we provided the first evidence that BMP6 circulates in WT mice and that iron increased the BMP6 serum level and the specific liver uptake of (99m)Tc-BMP6. In Bmp6-/- mice, iron challenge led to blunted activation of liver Smad signaling and hepcidin expression with a delay of 24 h, associated with increased Bmp5 and Bmp7 expression and increased Bmp2, 4, 5 and 9 expression in the duodenum. Liver Bmp7 expression and increased circulating BMP9 eventually contributed to the late hepcidin response. This was further supported by exogenous BMP7 therapy resulting in an effective hepcidin expression followed by a rapid normalisation of plasma iron values and restored osteopenia in Bmp6-/- mice.
  
  
  CONCLUSIONS
  In Bmp6-/- mice, iron activated endogenous compensatory mechanisms of other BMPs that were not sufficient for preventing hemochromatosis and bone loss. Administration of exogenous BMP7 was effective in correcting the plasma iron level and bone loss, indicating that BMP6 is an essential but not exclusive in vivo regulator of iron homeostasis.
authors.affiliation: Center for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000, Zagreb, Croatia, martina.pauk@mef.hr.
authors.forename: Martina
authors.initials: M
authors.lastname: Pauk
authors.forename: Lovorka
authors.initials: L
authors.lastname: Grgurevic
authors.forename: Jelena
authors.initials: J
authors.lastname: Brkljacic
authors.forename: Vera
authors.initials: V
authors.lastname: Kufner
authors.forename: Tatjana
authors.initials: T
authors.lastname: Bordukalo-Niksic
authors.forename: Kristina
authors.initials: K
authors.lastname: Grabusic
authors.forename: Genadij
authors.initials: G
authors.lastname: Razdorov
authors.forename: Dunja
authors.initials: D
authors.lastname: Rogic
authors.forename: Marijan
authors.initials: M
authors.lastname: Zuvic
authors.forename: Hermann
authors.initials: H
authors.lastname: Oppermann
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Lin
authors.forename: Sinisa
authors.initials: S
authors.lastname: Volarevic
authors.forename: Slobodan
authors.initials: S
authors.lastname: Vukicevic
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001851:Bone Diseases, Metabolic / Q000188:drug therapy*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D064451:Hepcidins / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000188:drug therapy*; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D064451:Hepcidins; D007501:Iron