• Administration of FVIIa-released extracellular vesicles from the endothelium markedly suppresses joint bleed-induced hemophilic arthropathy

  • miR10a in the extracellular vesicles is responsible for providing protection against the development of arthropathy following hemarthrosis

Repeated bleeding into joints in hemophilia leads to chronic inflammation that plays a central role in the pathogenesis of hemophilic arthropathy (HA). Our recent studies revealed that factor VIIa (FVIIa) treatment releases extracellular vesicles from the endothelium (eEVs) and FVIIa-released eEVs exhibit anti-inflammatory and barrier protective functions. The present study was undertaken to investigate the effect of FVIIa-released eEVs on HA and the mechanism of their protective effect. Joint bleeding in hemophilia (F8-/- ) mice was induced by a needle puncture injury. Injured mice were treated with saline, control eEVs, or FVIIa-released eEVs, and the changes in the knee joints were analyzed by gross examination of knees as well as histological and immunohistochemical analysis. Joint tissues were examined for evidence of synovial hyperplasia, macrophage infiltration, neoangiogenesis, cartilage degeneration, and chondrocyte apoptosis. The data showed that treatment of mice with control eEVs had no significant effect on the development of HA whereas treatment with FVIIa-released eEVs markedly reduced all pathological features of joint bleed-induced HA. Incorporation of microRNA10a (miR10a) inhibitor into FVIIa-released eEVs abrogated the protective effect of FVIIa-released eEVs on HA. More importantly, loading miR10a mimic into control eEVs conferred a protective effect. Administration of miR10a containing FVIIa-released eEVs or control eEVs loaded with miR10a mimic were found to abrogate joint bleed-induced IL-6 production in the synovium. miR10a in eEVs had no effect on hemostasis. Cumulatively, our data indicates that EVs containing miR10a that effectively suppress synovial inflammation would have immense therapeutic value in treating HA.

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First page of Factor VIIa-released extracellular vesicles attenuate joint bleed-induced hemophilic arthropathy
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