| First Author | Haxaire C | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 10 | Pages | 1064-1074 |
| PubMed ID | 29776906 | Mgi Jnum | J:265993 |
| Mgi Id | MGI:6201825 | Doi | 10.1182/blood-2017-12-820571 |
| Citation | Haxaire C, et al. (2018) Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-alpha pathway. Blood 132(10):1064-1074 |
| abstractText | 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-alpha (TNF-alpha) by the TNF-alpha convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-alpha 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-alpha 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-alpha levels in the affected joint of F8(-/-) mice. Moreover, inactivation of TNF-alpha 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-alpha 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. |
