Hypoxia increases Annexin A2 expression in osteoblastic cells via VEGF and ERK.
Vascular endothelial growth factor (VEGF)-stimulated angiogenesis is critical for endochondral ossification that occurs during bone development and bone repair. Under these circumstances, VEGF production appears to be driven by low oxygen tension, under the control of the hypoxia-inducible factor-α family of transcription factors (HIF-α). Annexin 2 (AnxA2) a calcium-dependent phospholipid binding protein has been implicated in VEGF-mediated retinal neovascularization and is upregulated by VEGF in choroid retinal endothelial cells. AnxA2 is also expressed in cells of the osteoblast lineage and chondrocytes and may play a role in matrix mineralization. In this paper, we examined the effects of hypoxia (1% O(2)) and VEGF on the expression of AnxA2 in osteoblastic MC3T3-E1 cells. Hypoxia, desferrioxamine (hypoxia mimetic), and recombinant VEGF all increased AnxA2 mRNA and protein levels in osteoblastic cells. The hypoxia-induced increase in AnxA2 was inhibited by a blocking antibody to VEGF-R1; however, VEGF(120), a VEGF-R1 agonist, demonstrated no influence upon Anxa2 expression. This suggests that VEGF induction of Annexin A2 is not mediated via VEGF-R1 agonism alone but by VEGF-R1 and Neuropilin-1 or Neuropilin-2 heterodimers. In addition, we demonstrated that VEGF-stimulated changes in AnxA2 expression via a pathway involving Src and MEK kinase. These data demonstrate that AnxA2 expression in osteoblasts is under the control of VEGF, which may have implications for both angiogenesis and bone mineralization under low oxygen conditions.
Genetos
Damian C
DC
Department of Anatomy, Cell Biology, and Physiology, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA.
Wong
Alice
A
Watari
Shinya
S
Yellowley
Clare E
CE
D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D017306:Annexin A2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D010100:Oxygen
Bone. 2002 Mar;30(3):472-7
11882460
Plast Reconstr Surg. 1999 Sep;104(3):738-47
10456527
J Biol Chem. 1996 Dec 20;271(51):32529-37
8955077
Stem Cells. 2003;21(6):661-9
14595126
J Cell Biol. 2002 Jun 10;157(6):1061-9
12045186
Biochem Biophys Res Commun. 1997 Oct 29;239(3):840-4
9367856
J Cell Biochem. 2009 Jan 1;106(1):127-38
19009559
Bone. 2008 Oct;43(4):734-9
18634913
J Exp Biol. 2003 Sep;206(Pt 17):2911-22
12878660
J Cell Biochem. 2009 May 15;107(2):233-9
19277991
Cells Tissues Organs. 2010;191(3):175-84
19690399
Philos Trans R Soc Lond B Biol Sci. 1975 Jul 17;271(912):261-72
239420
J Orthop Surg Res. 2009 Jun 16;4:19
19527527
Bone. 2004 Apr;34(4):680-8
15050899
J Cell Physiol. 2008 Sep;216(3):708-15
18366089
Steroids. 2002 Mar;67(3-4):235-46
11856547
Acta Orthop Scand. 1979 Dec;50(6 Pt 1):645-51
43659
Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):9656-61
12118119
Endocrinology. 2001 Feb;142(2):959-62
11159870
J Biol Chem. 2003 Sep 12;278(37):35564-73
12837752
J Cell Physiol. 2007 Jul;212(1):182-8
17370287
Nat Rev Mol Cell Biol. 2006 May;7(5):359-71
16633338
Mol Vis. 2009 Jun 17;15:1231-42
19536308
J Cell Sci. 2004 Jan 26;117(Pt 3):441-9
14679310
Am J Physiol. 1991 Jun;260(6 Pt 1):C1131-50
2058649
J Cell Biochem. 2001;81(1):82-92
11180399
Int J Hematol. 2009 Sep;90(2):177-185
19585213
Biochim Biophys Acta. 1997 Jun 27;1357(2):129-54
9223619
Microvasc Res. 2002 Nov;64(3):448-62
12453439
Am J Physiol. 1996 Oct;271(4 Pt 1):C1172-80
8897823
Nature. 2003 May 15;423(6937):332-6
12748651
J Clin Invest. 2007 Jun;117(6):1616-26
17549257
Am J Physiol Cell Physiol. 2010 Nov;299(5):C922-9
20660162
J Cell Biochem. 2005 Jul 1;95(4):827-39
15838884
J Bone Joint Surg Am. 1972 Mar;54(2):323-32
4651264
Blood. 2007 Jul 1;110(1):82-90
17360942
Am J Physiol. 1999 Sep;277(3):C598-602
10484347
Genes Dev. 2001 Nov 1;15(21):2865-76
11691837
Clin Cancer Res. 2004 Jul 1;10(13):4527-37
15240545
Bone. 2004 Sep;35(3):656-63
15336601
Mol Cell Biochem. 2010 Aug;341(1-2):9-16
20407807
J Biol Chem. 2006 Sep 8;281(36):25903-14
16847054
Acta Orthop Scand. 1979 Oct;50(5):519-25
43070
Am J Physiol Cell Physiol. 2000 Apr;278(4):C853-60
10751333
J Bone Joint Surg Am. 1976 Dec;58(8):1153-6
1002761
Acta Physiol Scand. 1984 Jun;121(2):127-31
6475543
J Cell Biochem. 2010 May 15;110(2):457-67
20336693
Endocrinology. 2000 May;141(5):1667-74
10803575
Endocrinology. 2002 Apr;143(4):1545-53
11897714
Cancer Res. 2000 Jan 15;60(2):203-12
10667560
Front Biosci. 2002 Feb 01;7:d341-8
11815288
Methods. 2001 Dec;25(4):402-8
11846609
J Orthop Res. 1992 Nov;10(6):807-12
1403294
Int J Cancer. 2007 Jan 1;120(1):111-20
17019707
J Bone Miner Res. 2008 Nov;23(11):1798-805
18597635
J Bone Miner Res. 1993 Oct;8(10):1201-10
8256657
Curr Pharm Des. 2007;13(35):3568-75
18220793
J Cell Biochem. 2007 Feb 15;100(3):679-92
16986113
Stem Cells. 2004;22(7):1263-78
15579645
Nat Med. 1999 Jun;5(6):623-8
10371499
Exp Mol Pathol. 2010 Apr;88(2):278-86
20079732
Blood. 2005 Feb 1;105(3):1068-77
15388583
Physiol Rev. 2002 Apr;82(2):331-71
11917092