Interactions between extracellular matrix proteins and the complement system - In the perspective of cartilage degradation in inflammatory joint diseases

Sammanfattning: Abstract: The joint diseases osteoarthritis and rheumatoid arthritis are characterized by destructive inflammatory processes that result in pathological changes of the joint tissues, including proteolytic degradation of cartilage and release of extracellular matrix proteins or fragments to the synovial fluid. The complement system, which is a part of the innate immune system, plays a central role in promoting the joint inflammation in these diseases. Potential activators of complement are certain extracellular matrix proteins that become exposed during cartilage degradation. Previous studies have revealed that several proteins from cartilage can activate or inhibit the complement system in vitro. In the present work, we describe the interactions between the complement system and additional extracellular matrix proteins, with the aim to better understand the role of endogenous ligands in the inflammatory process in joint diseases. We also describe the interactions between complement proteins and cartilage explants that have been subjected to inflammation-induced degradation. In paper I, we found that the G3 domain of aggrecan activates the classical pathway of complement. However, the activation of the terminal pathway is limited due to the simultaneous binding of factor H. Whether it activates complement when maintained in cartilage or when released into the synovial fluid remains to be elucidated. In paper II and III, we found that both proline/arginine-rich end leucine-rich repeat protein (PRELP) and the domain NC4 of collagen type IX, inhibit complement by preventing the assembly of the membrane attack complex. Further, PRELP also inhibits the assembly of the alternative pathway C3 convertase, while NC4 enhances the cofactor activities of C4b-binding protein and factor H, in the factor I-mediated cleavage of C4b and C3b. NC4 and fragments of PRELP can be detected in the synovial fluid of rheumatoid arthritis patients. Located in the synovial fluid or exposed on the cartilage surface, they might be important for limiting the complement activation, induced by other extracellular matrix proteins or other potential triggers. In Paper IV, we found that both the classical and the alternative pathways are activated on the surface of degraded cartilage explants, while components released from cartilage might have a weak, somewhat delayed, opposing role by inhibiting complement. The main activation seems to occur after the major loss of aggrecan from cartilage. In sum, several proteins of the extracellular matrix, as well as degraded cartilage have the potential to interact with the complement system, and may regulate the inflammatory processes in joint diseases.