The Potential Role of Protease Systems in Hemophilic Arthropathy

Haemophilic arthropathy is characterised by joint damage following recurrent joint bleeds frequently observed in patients affected by the clotting disorder haemophilia. Joint bleeds or haemarthroses trigger inflammation in the synovial tissue which promotes damage to the articular cartilage. The plasminogen activation system is integral to fibrinolysis, and urokinase plasminogen activator or uPA in particular is strongly upregulated following haemarthroses. uPA is a serine protease that catalyses the production of plasmin, a broad-spectrum protease that can degrade fibrin as well as proteins of the joint extracellular matrix and cartilage. Both uPA and plasmin are able to proteolytically generate active forms of matrix metalloproteinases (MMPs). The MMPs are a family of >20 proteases that are secreted as inactive proenzymes and are activated extracellularly. MMPs are involved in degradation of all types of collagen and proteoglycans that constitute the extracellular matrix, which provides structural support to articular cartilage. The MMPs have an established role in joint destruction following rheumatoid arthritis (RA). They degrade cartilage and bone, indirectly promoting angiogenesis. MMPs are also implicated in the pathology of osteoarthritis (OA) characterized by degradation of the cartilage matrix that precipitates joint damage and deformity. HA shares a number of overlapping pathological characteristics with RA and OA. Here we discuss how the plasminogen activation system and MMPs might exacerbate joint damage in HA, lending insight into novel possible therapeutic targets to reduce co-morbidity of haemophilia.