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

被引:17
作者
Akeel, Sara [1 ,2 ]
El-awady, Ahmed [1 ]
Hussein, Khaled [1 ,3 ]
El-Refaey, Mona [1 ]
Elsalanty, Mohammed [1 ]
Sharawy, Mohamed [1 ]
Al-Shabrawey, Mohamed [1 ,4 ]
机构
[1] Georgia Hlth Sci Univ, Coll Dent Med, Augusta, GA 30912 USA
[2] King Abdulaziz Univ, Sch Dent, Jeddah 21413, Saudi Arabia
[3] Natl Res Ctr, Giza, Egypt
[4] Mansoura Univ, Coll Med, Mansoura, Egypt
关键词
Osteoblasts; VEGF; rhBMP-2; IL6; PROMOTING ANGIOGENESIS; GENE-EXPRESSION; VEGF; DIFFERENTIATION; RECEPTORS; RATS;
D O I
10.1016/j.archoralbio.2011.10.002
中图分类号
R78 [口腔科学];
学科分类号
1003 ;
摘要
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-1 alpha 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). Conclusion: 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. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:445 / 452
页数:8
相关论文
共 35 条
[1]   Inhibition of NAD(P)H oxidase activity blocks vascular endothelial growth factor overexpression and neovascularization during ischemic retinopathy [J].
Al-Shabrawey, M ;
Bartoli, M ;
El-Remessy, AB ;
Platt, DH ;
Matragoon, S ;
Behzadian, MA ;
Caldwell, RW ;
Caldwall, RB .
AMERICAN JOURNAL OF PATHOLOGY, 2005, 167 (02) :599-607
[2]   VEGF and VEGF receptors are differentially expressed in chondrocytes [J].
Bluteau, Gilles ;
Julien, Marion ;
Magne, David ;
Mallein-Genin, Frederic ;
Weiss, Pierre ;
Daculsi, Guy ;
Guicheux, Jerome .
BONE, 2007, 40 (03) :568-576
[3]   Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways [J].
Botolin, Sergiu ;
McCabe, Laura R. .
JOURNAL OF CELLULAR BIOCHEMISTRY, 2006, 99 (02) :411-424
[4]   Bone morphogenetic protein-2 induces proinflammatory endothelial phenotype [J].
Csiszar, A ;
Ahmad, M ;
Smith, KE ;
Labinskyy, N ;
Gao, O ;
Kaley, G ;
Edwards, JG ;
Wolin, MS ;
Ungvari, Z .
AMERICAN JOURNAL OF PATHOLOGY, 2006, 168 (02) :629-638
[5]   Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A [J].
Deckers, MML ;
van Bezooijen, RL ;
van der Horst, G ;
Hoogendam, J ;
van der Bent, C ;
Papapoulos, SE ;
Löwik, CWGM .
ENDOCRINOLOGY, 2002, 143 (04) :1545-1553
[6]   Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation [J].
Deckers, MML ;
Karperien, M ;
van der Bent, C ;
Yamashita, T ;
Papapoulos, SE ;
Löwik, CWGM .
ENDOCRINOLOGY, 2000, 141 (05) :1667-1674
[7]   Parecoxib and Indomethacin Delay Early Fracture Healing: A Study in Rats [J].
Dimmen, Sigbjorn ;
Nordsletten, Lars ;
Madsen, Jan Erik .
CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, 2009, 467 (08) :1992-1999
[8]   VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells [J].
Garcia-Roman, Jonathan ;
Ibarra-Sanchez, Alfredo ;
Lamas, Monica ;
Gonzalez Espinosa, Claudia .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2010, 401 (02) :262-267
[9]   OXYGEN-DERIVED FREE-RADICALS STIMULATE OSTEOCLASTIC BONE-RESORPTION IN RODENT BONE INVITRO AND INVIVO [J].
GARRETT, IR ;
BOYCE, BF ;
OREFFO, ROC ;
BONEWALD, L ;
POSER, J ;
MUNDY, GR .
JOURNAL OF CLINICAL INVESTIGATION, 1990, 85 (03) :632-639
[10]   VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation [J].
Gerber, HP ;
Vu, TH ;
Ryan, AM ;
Kowalski, J ;
Werb, Z ;
Ferrara, N .
NATURE MEDICINE, 1999, 5 (06) :623-628