title: Effects of SU5416 and a vascular endothelial growth factor neutralizing antibody on wear debris-induced inflammatory osteolysis in a mouse model.
abstract: BACKGROUND
  The development of highly vascularized and inflammatory periprosthetic tissue characterizes the progress of aseptic loosening, a major complication of joint arthroplasty. Vascular endothelial growth factor (VEGF) is an important cell signaling protein involved in angiogenesis. The purpose of this study was to investigate whether R2/Fc (a VEGF neutralizing antibody) and SU5416 (a VEGF receptor II [Flk-1] inhibitor) could ameliorate particle-induced inflammatory osteolysis in a mouse model.
  
  
  METHODS
  Ultrahigh molecular weight polyethylene (UHMWPE) particles were introduced into established air pouches in BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. Drug treatment was started 2 weeks after bone implantation, and mice without drug treatment were included as controls. Pouch tissues were harvested 4 weeks after bone implantation for molecular and histological analysis, and implanted bone degradation was analyzed by microcomputed tomography.
  
  
  RESULTS
  Exposure to UHMWPE particles induced inflammatory osteolysis, which was associated with increased expression of VEGF/Flt-1 proteins. Treatment with R2/Fc significantly improved UHMWPE particle-induced inflammatory osteolysis, and reduced the expression of VEGF/Flt-1 proteins. However, SU5416 treatment showed no effect on UHMWPE particle-induced inflammatory osteolysis.
  
  
  CONCLUSIONS
  Our findings indicate that VEGF signaling exerts a regulatory effect on the development of UHMWPE-induced inflammatory osteolysis, through its unique Flt-1, rather than Flk-1, receptor located on monocyte/macrophage cell lineages. These data provide a biological rationale for a VEGF/Flt-1-targeted treatment strategy, especially during the early stages of the wear debris-induced inflammatory response.
authors.affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Ren
authors.forename: Renwen
authors.initials: R
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wooley
authors.forename: Monica
authors.initials: M
authors.lastname: Hawkins
authors.forename: David C
authors.initials: DC
authors.lastname: Markel
references.citation: Scand J Rheumatol. 2004;33(5):349-57
references.pmid: 15513686
references.citation: J Clin Invest. 1998 Jan 1;101(1):40-50
references.pmid: 9421464
references.citation: J Pathol. 2000 Aug;191(4):426-33
references.pmid: 10918218
references.citation: J Pharm Pharmacol. 2001 Dec;53(12):1629-36
references.pmid: 11804393
references.citation: Blood. 1996 Apr 15;87(8):3336-43
references.pmid: 8605350
references.citation: Blood. 2003 Aug 1;102(3):795-801
references.pmid: 12649163
references.citation: J Rheumatol. 2007 Jan;34(1):27-35
references.pmid: 17216676
references.citation: Birth Defects Res C Embryo Today. 2003 Nov;69(4):363-74
references.pmid: 14745976
references.citation: Clin Orthop Relat Res. 2002 Dec;(405):138-43
references.pmid: 12461365
references.citation: J Bone Miner Res. 2004 Feb;19(2):200-6
references.pmid: 14969389
references.citation: J Bone Miner Res. 2001 Feb;16(2):338-47
references.pmid: 11204434
references.citation: J Exp Med. 1994 Jul 1;180(1):341-6
references.pmid: 8006592
references.citation: J Biol Chem. 2003 Oct 10;278(41):39548-57
references.pmid: 12893832
references.citation: Arthritis Rheum. 2003 Aug;48(8):2173-7
references.pmid: 12905470
references.citation: Blood. 2001 Feb 1;97(3):785-91
references.pmid: 11157498
references.citation: Ann Rheum Dis. 1995 Mar;54(3):201-8
references.pmid: 7538286
references.citation: J Biol Chem. 2003 Dec 5;278(49):48745-53
references.pmid: 14506249
references.citation: J Bone Joint Surg Am. 2002 Feb;84(2):171-7
references.pmid: 11861721
references.citation: J Mater Sci Mater Med. 2001 Oct-Dec;12(10-12):1069-73
references.pmid: 15348367
references.citation: J Orthop Res. 2002 Sep;20(5):1031-7
references.pmid: 12382970
references.citation: J Immunol. 2002 Jun 1;168(11):5824-31
references.pmid: 12023386
references.citation: Gene Ther. 2004 Feb;11(4):402-7
references.pmid: 14724679
references.citation: Biomaterials. 2006 Oct;27(30):5161-9
references.pmid: 16814378
references.citation: Biomaterials. 2002 Jan;23(2):517-26
references.pmid: 11761173
references.citation: J Biomed Mater Res. 1999;48(6):889-98
references.pmid: 10556856
references.citation: J Exp Med. 1999 Jul 19;190(2):293-8
references.pmid: 10432291
references.citation: Oncologist. 2002;7(6):569-70
references.pmid: 12490744
references.citation: J Immunol. 2003 Nov 1;171(9):4853-9
references.pmid: 14568965
references.citation: J Dent Res. 2001 Oct;80(10):1880-3
references.pmid: 11706945
references.citation: Ann N Y Acad Sci. 2002 Dec;979:80-93
references.pmid: 12543719
references.citation: Blood. 2004 Aug 15;104(4):1048-57
references.pmid: 15100155
references.citation: J Bone Joint Surg Am. 2003 Jun;85(6):1066-72
references.pmid: 12784004
references.citation: J Bone Miner Res. 2003 Sep;18(9):1573-83
references.pmid: 12968666
references.citation: Blood. 2003 Jul 1;102(1):161-8
references.pmid: 12649136
references.citation: J Biol Chem. 1994 Oct 28;269(43):26988-95
references.pmid: 7929439
references.citation: FEBS Lett. 2000 May 12;473(2):161-4
references.pmid: 10812066
references.citation: Cytokine. 2000 Oct;12(10):1575-9
references.pmid: 11023677