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- Publisher Website: 10.1182/blood-2017-12-820571
- Scopus: eid_2-s2.0-85052853141
- PMID: 29776906
- WOS: WOS:000443840200013
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Article: Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway
Title | Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway |
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Authors | |
Issue Date | 2018 |
Citation | Blood, 2018, v. 132, n. 10, p. 1064-1074 How to Cite? |
Abstract | © 2018 by The American Society of Hematology. 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-a (TNF-a) by the TNF-a convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-a 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-a 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 (F82/2 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-a levels in the affected joint of F82/2 mice. Moreover, inactivation of TNF-a or iRhom2 in F82/2 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-a 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. |
Persistent Identifier | http://hdl.handle.net/10722/293096 |
ISSN | 2023 Impact Factor: 21.0 2023 SCImago Journal Rankings: 5.272 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Haxaire, Coline | - |
dc.contributor.author | Hakobyan, Narine | - |
dc.contributor.author | Pannellini, Tania | - |
dc.contributor.author | Carballo, Camila | - |
dc.contributor.author | McIlwain, David | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Rodeo, Scott | - |
dc.contributor.author | Acharya, Suchitra | - |
dc.contributor.author | Li, Daniel | - |
dc.contributor.author | Szymonifka, Jackie | - |
dc.contributor.author | Song, Xiangqian | - |
dc.contributor.author | Monette, Sébastien | - |
dc.contributor.author | Srivastava, Alok | - |
dc.contributor.author | Salmon, Jane E. | - |
dc.contributor.author | Blobel, Carl P. | - |
dc.date.accessioned | 2020-11-17T14:57:52Z | - |
dc.date.available | 2020-11-17T14:57:52Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Blood, 2018, v. 132, n. 10, p. 1064-1074 | - |
dc.identifier.issn | 0006-4971 | - |
dc.identifier.uri | http://hdl.handle.net/10722/293096 | - |
dc.description.abstract | © 2018 by The American Society of Hematology. 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-a (TNF-a) by the TNF-a convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-a 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-a 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 (F82/2 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-a levels in the affected joint of F82/2 mice. Moreover, inactivation of TNF-a or iRhom2 in F82/2 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-a 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. | - |
dc.language | eng | - |
dc.relation.ispartof | Blood | - |
dc.title | Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1182/blood-2017-12-820571 | - |
dc.identifier.pmid | 29776906 | - |
dc.identifier.pmcid | PMC6128089 | - |
dc.identifier.scopus | eid_2-s2.0-85052853141 | - |
dc.identifier.volume | 132 | - |
dc.identifier.issue | 10 | - |
dc.identifier.spage | 1064 | - |
dc.identifier.epage | 1074 | - |
dc.identifier.eissn | 1528-0020 | - |
dc.identifier.isi | WOS:000443840200013 | - |
dc.identifier.issnl | 0006-4971 | - |