title: Recombinant bone morphogenetic protein-2 induces up-regulation of vascular endothelial growth factor and interleukin 6 in human pre-osteoblasts: role of reactive oxygen species.
abstract: OBJECTIVE
  Bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) have been reported in many studies to play a major role in the communication between endothelial cells and osteoblasts. The inflammatory reaction and relative hypoxia at the site of bone injury are the first stages of the fracture repair. rhBMP-2 has been used extensively in spinal fusion and reconstruction of maxillofacial bone defects with main complication is the formation of seroma. The aim of this study was to test whether rhBMP-2 regulates the expression of the angiogenic and inflammatory mediators in pre-osteoblasts via generating reactive oxygen species (ROS).
  
  
  METHODS
  rhBMP-2 effect on angiogenesis and inflammatory genes was assessed using normal human osteoblasts (NHOst). Angiogenesis genes were measured using angiogenic PCR array. VEGF and IL6 production were analysed using ELISA kit and real-time PCR. ROS production was assessed using dihydroethidine and dichlorofluorescein staining and lipid peroxidation. HIF-1α immunoreactivity was performed using immunofluorescence staining.
  
  
  RESULTS
  There was an increase in the pro-angiogenic and -inflammatory genes as well as VEGF and IL6 protein expression in NHOst by rhBMP-2. This increase in VEGF and IL6 was blocked by the ROS scavenger N-acetyl cysteine (NAC).
  
  
  CONCLUSIONS
  The regulatory effect of rhBMP-2 on angiogenesis and inflammation is mediated through a ROS-dependent mechanism, which involves upregulation of crucial angiogenic and inflammatory mediators such as VEGF and IL6. These findings highlight the need for future studies to identify new therapeutic targets downstream from rhBMP-2 to potentiate its beneficial effect or limit its complications such as seroma formation.
authors: Oral Biology and Anatomy, College of Dental Medicine, Georgia Health Sciences University, Augusta, GA 30912, United States.
authors: Sara
authors: S
authors: Akeel
authors: Ahmed
authors: A
authors: El-Awady
authors: Khaled
authors: K
authors: Hussein
authors: Mona
authors: M
authors: El-Refaey
authors: Mohammed
authors: M
authors: Elsalanty
authors: Mohamed
authors: M
authors: Sharawy
authors: Mohamed
authors: M
authors: Al-Shabrawey
mesh_terms: D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D015227:Lipid Peroxidation; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015415:Biomarkers; D055396:Bone Morphogenetic Protein 2; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C499469:recombinant human bone morphogenetic protein-2