Affiliation:
1. The Third Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University
2. First Teaching Hospital of Xinjiang Medical University
3. The Sixth Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University
Abstract
Abstract
Hemophilia frequently results in intra-articular bleeding, leading to substantial iron accumulation in the synovium, which facilitates M1 macrophage polarization and triggers synovitis. While current therapeutic approaches predominantly involve surgery, this study seeks to identify small molecule drug targets for treating hemophilic synovitis. In vitro RAW264.7 macrophages were categorized into five groups based on varying concentrations of deferoxamine: Ctrl, Fe, DFO1, DFO2, and DFO3. Rats were divided into five groups for differing doses of deferoxamine intra-articular injections: A-Ctrl, A-Fe, A-DFO1, A-DFO2, and A-DFO3. Excluding the A-Ctrl group, all other groups received injections of autologous venous blood into their knee joints. The relevant indexes were detected by experiment. In vitro experiments indicated no iron overload in the macrophages of any deferoxamine group, with morphological analyses showing no shift towards an M1 polarization phenotype. qPCR showed no significant change in iNOS expression, and Western Blot analysis confirmed no significant increase in iNOS and p-4E-BP1 proteins. ELISA results indicated stable levels of TNF-α and IL-6 in the supernatant. In animal studies, Prussian blue staining revealed a concentration-dependent reduction in iron deposition in the synovium across groups. Immunohistochemistry highlighted significantly higher F4/80 protein expression in the synovium of each treatment group compared to the A-Ctrl. With increased deferoxamine concentrations, iNOS and p-4E-BP1 protein expressions significantly declined, whereas Arg-1 expression notably increased, all in a concentration-dependent fashion. Iron overload within synovial cells may drive M1 macrophage polarization via phosphorylation regulation of 4E-BP1 in the mTORC1-p70S6K/4E-BP1 pathway, leading to joint cartilage damage.
Publisher
Research Square Platform LLC
Reference42 articles.
1. Haemophilic arthritis;Madhok R;Ann Rheum Dis,1991
2. Haemophilic arthropathy: A narrative review on the use of intra-articular drugs for arthritis;Buccheri E;Haemophilia,2019
3. Blocking hemophilic arthropathy;Shi Q;Blood,2022
4. Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia;Srivastava A;Haemophilia,2013
5. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy;Valentino LA;J Thromb Haemost,2010