Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway
| العنوان: | Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway |
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| المؤلفون: | Sebastien Monette, Daniel Li, Xiangqian Song, Coline Haxaire, Tak W. Mak, Scott A. Rodeo, Tania Pannellini, David R. McIlwain, Camila B. Carballo, Narine Hakobyan, Carl P. Blobel, Alok Srivastava, Jane E. Salmon, Suchitra S. Acharya, Jackie Szymonifka |
| المصدر: | Blood. 132:1064-1074 |
| بيانات النشر: | American Society of Hematology, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | musculoskeletal diseases, 0301 basic medicine, Immunology, Osteoporosis, Inflammation, ADAM17 Protein, 030204 cardiovascular system & hematology, Hemophilia A, Biochemistry, Thrombosis and Hemostasis, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, Synovitis, Hemarthrosis, medicine, Animals, Bone Resorption, Mice, Knockout, Factor VIII, Tumor Necrosis Factor-alpha, business.industry, Cell Biology, Hematology, medicine.disease, Osteopenia, Disease Models, Animal, 030104 developmental biology, Rheumatoid arthritis, Female, Tumor necrosis factor alpha, medicine.symptom, Carrier Proteins, business, Signal Transduction |
| الوصف: | Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is inappropriate release of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by the TNF-α convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-α also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNF-α shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic FVIII-deficient mice (F8(−/−) mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture–induced bleeding leads to increased TNF-α levels in the affected joint of F8(−/−) mice. Moreover, inactivation of TNF-α or iRhom2 in F8(−/−) mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNF-α pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this proinflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients. |
| تدمد: | 1528-0020 0006-4971 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::57bfac7434cafca80fb650d7982cf6e4Test https://doi.org/10.1182/blood-2017-12-820571Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....57bfac7434cafca80fb650d7982cf6e4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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