Journal
BLOOD
Volume 117, Issue 8, Pages 2484-2493Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-05-284653
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Funding
- Hemophilia of Georgia Foundation
- Doris Duke Charitable Foundation
- Hope Street Kids
- ASCO
- Butler Foundation
- Michael Cuccione Foundation
- National Foundation for Cancer Research
- Hartwell Foundation
- Malcolm Hewitt Wiener Foundation
- Nancy C. and Daniel P. Paduano Foundation
- American Hellenic Educational Progressive Foundation
- Charles and Meryl Witmer Family Foundation
- Stavros S. Niarchos Foundation
- Champalimaud Foundation
- Susan G. Komen for the Cure
- Children's Cancer and Blood Foundation Laboratories
- A. P. Alexander Family donation for hemophilia research
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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-1 alpha mRNA with HIF-1 alpha 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. (Blood. 2011;117(8):2484-2493)
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