Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: Implications for fracture healing

被引:252
作者
Bouletreau, PJ
Warren, SM
Spector, JA
Peled, ZM
Gerrets, RP
Greenwald, JA
Longaker, MT
机构
[1] Stanford Univ, Sch Med, Dept Surg, Stanford, CA 94305 USA
[2] NYU, Ctr Med, Dept Surg, New York, NY USA
关键词
D O I
10.1097/00006534-200206000-00033
中图分类号
R61 [外科手术学];
学科分类号
摘要
The endothelium is a metabolically active secretory tissue, capable of responding to a wide array of environmental stimuli. Hypoxia and vascular endothelial growth factor (VEGF) are two components, of the putative fracture micro-environment investigated the role of hypoxia and VEGF on endothelial cell activation as it relates to the bone repair process. It was hypothesized that endothelial cells may have all important osteogenic role in fracture healing through the production of bone morphogenetic protein-2 (BMP-2), an osteogenic cytokine at the fracture site. Therefore, BMP-2 mRNA and protein expression in endothelial cells tinder hypoxia and/or VEGF treatment was studied. The authors observed a 2-fold to 3-fold up-regulation of BMP-2 mRNA expression in bovine capillary endothelial cells and human microvascular endothelial cells stimulated with hypoxia of rhVEGF. Furthermore, the combined effects of hypoxia and rhVEGF appeared to he additive on BMP-2 mRNA expression in bovine capillary endothelial cells. Actinomycin D and cycloheximide studies suggested that the increased mRNA expression was transcriptionally regulated, BMP-2 protein expression was up-regulated after 24 and 48 hours of treatment with either hypoxia or rhVEGF in bovine capillary endothelial cells. Surprisingly, the data suggest that endothelial cells may play not only all angiogenic role bolt also all osteogenic role by a direct stimulation of the osteoblasts through the enhanced expression of a potent osteogenic factor, BMP-2, at the fracture site.
引用
收藏
页码:2384 / 2397
页数:14
相关论文
共 66 条
[1]   ERYTHROPOIETIN HAS A MITOGENIC AND POSITIVE CHEMOTACTIC EFFECT ON ENDOTHELIAL-CELLS [J].
ANAGNOSTOU, A ;
LEE, ES ;
KESSIMIAN, N ;
LEVINSON, R ;
STEINER, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (15) :5978-5982
[2]   HYPOXIA INDUCES AP-1-REGULATED GENES AND AP-1 TRANSCRIPTION FACTOR-BINDING IN HUMAN ENDOTHELIAL AND OTHER CELL-TYPES [J].
BANDYOPADHYAY, RS ;
PHELAN, M ;
FALLER, DV .
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1995, 1264 (01) :72-78
[3]  
BERNSTEIN LR, 1982, J CELL SCI, V56, P71
[4]   BONE MORPHOGENETIC PROTEIN EXPRESSION IN HUMAN ATHEROSCLEROTIC LESIONS [J].
BOSTROM, K ;
WATSON, KE ;
HORN, S ;
WORTHAM, C ;
HERMAN, IM ;
DEMER, LL .
JOURNAL OF CLINICAL INVESTIGATION, 1993, 91 (04) :1800-1809
[5]   OXYGEN-TENSION OF HEALING FRACTURES IN RABBIT [J].
BRIGHTON, CT ;
KREBS, AG .
JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME, 1972, A 54 (02) :323-&
[6]   EARLY HISTOLOGICAL AND ULTRASTRUCTURAL-CHANGES IN MEDULLARY FRACTURE CALLUS [J].
BRIGHTON, CT ;
HUNT, RM .
JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME, 1991, 73A (06) :832-847
[7]   Oxygen sensing and molecular adaptation to hypoxia [J].
Bunn, HF ;
Poyton, RO .
PHYSIOLOGICAL REVIEWS, 1996, 76 (03) :839-885
[8]  
Carlevaro MF, 2000, J CELL SCI, V113, P59
[9]   IDENTIFICATION OF TRANSFORMING GROWTH-FACTOR-BETA FAMILY MEMBERS PRESENT IN BONE-INDUCTIVE PROTEIN PURIFIED FROM BOVINE BONE [J].
CELESTE, AJ ;
IANNAZZI, JA ;
TAYLOR, RC ;
HEWICK, RM ;
ROSEN, V ;
WANG, EA ;
WOZNEY, JM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (24) :9843-9847
[10]   ROLE OF VASCULAR ENDOTHELIAL-CELLS IN BONE BIOLOGY [J].
COLLINOSDOBY, P .
JOURNAL OF CELLULAR BIOCHEMISTRY, 1994, 55 (03) :304-309