title: Systemically available bone morphogenetic protein two and seven affect bone metabolism.
abstract: OBJECTIVE
  Bone morphogenetic protein (BMP)-2 and -7 are used in patients with long-bone fractures, nonunions and spinal fusions. It is unknown whether their potential systemic bioavailability following local bone administration might affect skeletal metabolism. To answer this question, we examined effects of systemically administered BMP-2 and -7 on bone in a newly developed rat model with a low level of calciotropic hormones.
  
  
  METHODS
  Removal of thyroid and parathyroid glands (TPTx) in rats resulted in a decreased level of calciotropic hormones and subsequent bone loss assessed by micro computed tomography (micro-CT) and measurement of serum bone formation and resorption markers, including osteocalcin, C-telopeptide, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand. Results were complemented with in vitro studies on osteoblast and osteoclast activity by both BMP-2 and -7. The doses used were calculated from published pharmacodynamic studies and bioavailability results from preclinical BMP-2 and -7 studies.
  
  
  RESULTS
  TPTx resulted in bone loss, which was restored by systemic administration of 10-70 μg/kg of BMP-2 and 10-250 μg/kg of BMP-7. BMP-2 showed a higher capacity for enhancing trabecular microarchitecture, whereas BMP-7 augmented trabecular thickness. In vitro experiments revealed that BMP-2 and -7 when uncoupled increased the number and activity of both osteoblasts and osteoclasts.
  
  
  CONCLUSIONS
  Surprisingly, both BMP-2 and -7 showed an increased bone volume in an in vivo environment of low calciotropic hormones. Locally administered BMP-2 and -7 from bone devices might become partially available in circulation but will not mediate systemic bone loss.
authors.affiliation: Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, Šalata 11, Zagreb, 10000, HR, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Dumic-Cule
authors.forename: Jelena
authors.initials: J
authors.lastname: Brkljacic
authors.forename: Dunja
authors.initials: D
authors.lastname: Rogic
authors.forename: Tatjana
authors.initials: T
authors.lastname: Bordukalo Niksic
authors.forename: Ana
authors.initials: A
authors.lastname: Tikvica Luetic
authors.forename: Natasa
authors.initials: N
authors.lastname: Draca
authors.forename: Vera
authors.initials: V
authors.lastname: Kufner
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trkulja
authors.forename: Lovorka
authors.initials: L
authors.lastname: Grgurevic
authors.forename: Slobodan
authors.initials: S
authors.lastname: Vukicevic
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D066298:In Vitro Techniques; D023421:Models, Animal; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C525720:Bmp2 protein, rat; C525821:Bmp7 protein, rat; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D053244:Osteoprotegerin; D053245:RANK Ligand