Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway Journal Article


Authors: Haxaire, C.; Hakobyan, N.; Pannellini, T.; Carballo, C.; McIlwain, D.; Mak, T. W.; Rodeo, S.; Acharya, S.; Li, D.; Szymonifka, J.; Song, X.; Monette, S.; Srivastava, A.; Salmon, J. E.; Blobel, C. P.
Article Title: Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway
Abstract: 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. © 2018 by The American Society of Hematology.
Journal Title: Blood
Volume: 132
Issue: 10
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-09-06
Start Page: 1064
End Page: 1074
Language: English
DOI: 10.1182/blood-2017-12-820571
PROVIDER: scopus
PMCID: PMC6128089
PUBMED: 29776906
DOI/URL:
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
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  1. Sebastien Monette
    75 Monette