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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-02-0390.
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Blood, 1 August 2002, Vol. 100, No. 3, pp. 912-916
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
c-myc proto-oncogene expression in hemophilic
synovitis: in vitro studies of the effects of iron and
ceramide
Fei-Qiu Wen,
Adnan A. Jabbar,
Yi-Xin Chen,
Tamara Kazarian,
Dharmesh A. Patel, and
Leonard A. Valentino
From the Departments of Pediatrics and
Immunology/Microbiology, Rush Children's Hospital and Rush University,
Chicago, IL.
Hemophilia is a rare congenital bleeding disorder that is due to
the deficiency of blood coagulation factor VIII or IX. Recurrent musculoskeletal bleeding is common and bleeding into joints results in
a chronic inflammatory condition termed hemophilic synovitis. This
destructive process is characterized by hemosiderin deposition in the
superficial and deeper layers of the synovial membrane as well as a
proliferation of synovial fibroblasts and vascular cells. The
hyperplastic synovium and neovascular changes are reminiscent of the
histopathologic appearance observed in malignant tissues. Indeed, the
benign hyperplastic synovium in patients with hemophilia displays
similar invasive and destructive behaviors suggesting the possibility
of analogous disturbances in growth control and locally invasive
mechanisms. Iron plays a role in malignant cell growth, local invasion,
and tumor progression, possibly due to changes in the expression of the
proto-oncogene, c-myc. We hypothesized that iron
plays a similar role in hemophilic synovitis. To explore this
hypothesis, we investigated the in vitro effects of iron on the
proliferation of a primary, human synovial fibroblast cell (HSFC) line
and the involvement of c-myc in this process. We also examined the role of ceramide, a sphingolipid capable of inducing apoptosis in this model system. HSFC proliferation was increased in a
dose-dependent fashion and c-myc expression was enhanced by
ferric citrate compared to sodium citrate control. Ceramide prevented
both the iron-induced increases in HSFC proliferation and
c-myc expression. These results indicate that iron probably plays a role in the proliferative changes observed in hemophilic joint
disease and that aberrant expression of c-myc may underlie the iron effects. Furthermore, these results suggest that there may be
a therapeutic role for ceramide in reversing these changes.
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