Effect of Blood on Synovial Joint Tissues: Potential Role of Ferroptosis

Recurrent bleeding in the synovial joint, such as the knee, can give rise to chronic synovitis and degenerative arthritis, which are major causes of morbidity. Whereas chronic arthropathy affects one-fifth of hemophiliacs, conditions such as rheumatoid arthritis (RA), periarticular and articular fractures, osteochondral autograft transplantation surgery, and anterior cruciate ligament (ACL) injury are also associated with joint bleeding. Synovial joint trauma is associated with inflammation, acute pain, bloody joint effusion, and knee instability. Clinically, some physicians have advocated for blood aspiration from the joint post-injury to mitigate the harmful effects of bleeding. Despite the significant potential clinical impact of joint bleeding, the mechanism(s) by which joint bleeding, acute or microbleeds, leads to deleterious changes to the synovial joint remains understudied. This review will address the impact of blood on synovial joint tissues observed from in vitro and in vivo studies. While the deleterious effects of blood on cartilage and synovium are well-described, there are much fewer reports describing the negative effects of blood on the meniscus, cruciate ligaments, and subchondral bone. Based on our studies of blood in co-culture with chondrocytes/cartilage, we raise the possibility that ferroptosis, an iron-dependent, nonapoptotic form of regulated cell death, plays a contributing role in mediating hemophilic arthropathy (HA) and may represent a therapeutic target in reducing the negative impact of joint bleeds.