Blood-induced joint damage: novel targets for therapy

-induced joint damage can occur due to a trauma but also during surgery when blood leaks into the joint cavity. Besides that, it is one of the major causes of morbidity amongst haemophilia patients. The aims of this thesis were to further unravel the pathogenesis of blood-induced joint damage and to develop new strategies to prevent or treat this joint damage. To achieve these aims several in vitro and in vivo models were used. This thesis shows in an in vivo model that, in contrast to intermittent exposure, a 4-day continuous blood exposure twice in 4 weeks leads to prolonged cartilage damage. This prolonged damage is independent of the level of synovial inflammation. It appears that there is a threshold to induce irreversible joint damage, which is only reached by a more intensive continuous blood load. Furthermore, coagulating blood causes more cartilage damage and synovial inflammation than anticoagulated blood. This aggravation of joint damage by coagulation is also seen in vitro where coagulated blood results in more cartilage damage compared to anticoagulated blood. If the consequences of blood-exposure could be visualized very shortly after a joint bleed, instead of after years, it would allow prevention or treatment at a more individual patient level. One way to monitor joint damage is by measuring biochemical markers. It is demonstrated that on average a single joint bleed increases biochemical markers of joint tissue damage (CTXII, COMP, C1,2C, and CS846) in a small group of patients. Blood-induced damage to the cartilage matrix is limited by IL-4 as well as IL-10. Adding IL-4 to IL-10 leads to a more pronounced protective effect than IL-10 alone, suggesting that a combination of the two cytokines might have additional value. Besides the effects on proteoglycan turnover also IL-4, and to a lesser extent IL-10, limits production of proinflammatory cytokines by blood monocytes and limits apoptosis of chondrocytes. However, there is only a short time window of 4-8 hours after onset of the joint bleed in which IL-4 plus IL-10 can still limit blood-induced cartilage damage. The damage can be almost fully prevented by shortening the time span of blood exposure by aspirating the blood within 24 hours. In an in vivo haemophilia mouse model, a single intra-articular injection directly after a joint bleed ameliorates cartilage degeneration, but does not diminish synovial inflammation when analysed after 30 days. The reason for a partial effect on cartilage damage and the absence of an effect on inflammation could be due to low bioavailability of the cytokines. A fusion protein combining IL-4 and IL-10, called the ‘IL4-10 synerkine’ and having the same effects on blood-induced cartilage damage, might tackle this problem. For patients with heavily damaged joints, joint distraction can be used as an alternative to surgical treatments like ankle arthrodesis or total joint replacement. In the haemophilia patients treated, joint distraction improves their functional health and participation in society and autonomy, diminishes their pain, and results in evident structural improvement of the joint.