Abstract:
Hemophilia is an X chromosome-linked bleeding disorder disease caused by a lack of coagulation factor. Hemophilia patients suffer from spontaneous bleedings that may occur in different organs and tissues. Hemophilic arthropathy (HA) is the primary etiology leading to disability in hemophilia patients which is caused by the recurrent bleeding in the joints. Over expression of pro-inflammatory cytokines has been putatively recognized as one of the mechanisms. In the progression of HA, pro-inflammatory cytokines serve as signaling mediators, among which TNFα is one of the most important. As a receptor of TNFα, sTNFR (soluble tumor necrosis factor receptor) specifically binds to TNFα
and antagonizes its pro-inflammtory effect. To investigate the therapeutic effect of local long-term TNFα expression on HA, hemophilia B mice were intra-articularly injected with rAAV5-TNFR:Fc. In the present study, plasmid pAAV-TNFR:Fc was constructed and used for the package of rAAV5-TNFR:Fc. Transgene expression mediated by infection
in vitro and
in vivo were confirmed by western blot. Then hemophilia B mice divided into prophylaxis group and treatment group were intraarticularly injected with rAAV5-TNFR:Fc, and 6 weeks after HA was induced, joint tissues were collected for RNA extract to measure the mRNA expression level of TNFα
、IL-1β、IL-6 and IL-10. The pathology changes of joints were also graded by histology and the scorings of synovitis arthritis, macrophage infiltration and neovascularization were obtained. The results suggested that, 42 d after joints hemarthrosis induction, sTNFR expression in joints persisted. The pathological sequela in two groups were reduced to different degrees after rAAV5-TNFR:Fc local delivery and delivery as a prophylaxis showed better outcome than as a treatment. It was concluded that recombinant adeno-associated virus mediated soluble tumor necrosis factor receptor could be a therapeutic approach for HA treatment.