title: Neoangiogenesis contributes to the development of hemophilic synovitis.
abstract: Joint arthropathy secondary to recurrent hemarthroses remains a debilitating complication of hemophilia despite the use of prophylactic factor concentrates. Increased vascularity and neoangiogenesis have been implicated in the progression of musculoskeletal disorders and tumor growth. We hypothesized that de novo blood vessel formation could play a major role in the pathogenesis of hemophilic joint disease (HJD). We observed a 4-fold elevation in proangiogenic factors (vascular endothelial growth factor-A [VEGF-A], stromal cell-derived factor-1, and matrix metalloprotease-9) and proangiogenic macrophage/monocyte cells (VEGF(+)/CD68(+) and VEGFR1(+)/CD11b(+)) in the synovium and peripheral blood of HJD subjects along with significantly increased numbers of VEGFR2(+)/AC133(+) endothelial progenitor cells and CD34(+)/VEGFR1(+) hematopoietic progenitor cells. Sera from HJD subjects induced an angiogenic response in endothelial cells that was abrogated by blocking VEGF, whereas peripheral blood mononuclear cells from HJD subjects stimulated synovial cell proliferation, which was blocked by a humanized anti-VEGF antibody (bevacizumab). Human synovial cells, when incubated with HJD sera, could elicit up-regulation of HIF-1α mRNA with HIF-1α expression in the synovium of HJD subjects, implicating hypoxia in the neoangiogenesis process. Our results provide evidence of local and systemic angiogenic response in hemophilic subjects with recurrent hemarthroses suggesting a potential to develop surrogate biologic markers to identify the onset and progression of hemophilic synovitis.
authors.affiliation: Department of Pediatric Hematology/Oncology, National Institutes of Health, Bethesda, MD, USA. sacharya@nshs.edu
authors.forename: Suchitra S
authors.initials: SS
authors.lastname: Acharya
authors.forename: Rosandra N
authors.initials: RN
authors.lastname: Kaplan
authors.forename: Dan
authors.initials: D
authors.lastname: Macdonald
authors.forename: Oluwa T
authors.initials: OT
authors.lastname: Fabiyi
authors.forename: Donna
authors.initials: D
authors.lastname: DiMichele
authors.forename: David
authors.initials: D
authors.lastname: Lyden
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D006395:Hemarthrosis / Q000209:etiology* / Q000503:physiopathology; D006467:Hemophilia A / Q000150:complications*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000150:complications* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D012008:Recurrence; D012189:Retrospective Studies; D013583:Synovial Membrane / Q000737:chemistry; D013585:Synovitis / Q000209:etiology* / Q000503:physiopathology; D015854:Up-Regulation / Q000235:genetics; D042442:Vascular Endothelial Growth Factors / Q000032:analysis / Q000097:blood
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042442:Vascular Endothelial Growth Factors