Osteoarthritis is an inflammatory disorder driven by complement
Osteoarthritis has long been thought by many to be caused by mechanical stress on joints but experienced clinicians know that the degree of pain experienced corresponds to the amount of inflammation. Brilliant research recently published in Nature Medicine offers further evidence that osteoarthritis is an inflammatory disorder driven by the complement system, a part of the innate immune system. The authors state:
"Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of “wear and tear”. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis."
They used proteomic and transcriptomic analyses of synovial fluids and membranes from humans with osteoarthritis and found that the presence and activity of complement is abnormally high in humans with osteoarthritic joints. They the authors investigated the role of complement in the pathogenesis of osteoarthritis by performing a medial meniscectomy (removal of a portion of the knee cartilage) on their subject animals. They chose to do this because in humans tearing of the meniscus often requires a medial meniscectomy, and this is a well-known risk factor for knee osteoarthritis. C5 is a critical element in the complement cascade, so they surgically induced osteoarthritis in C5-deficient and C5-sufficient (C5+) mice...Sixteen weeks after surgery, C5− mice exhibited substantially less cartilage loss, osteophyte formation, and synovitis than did C5+ mice...
"Using mice genetically deficient in C5, C6, or CD59a, we show that complement, and specifically the membrane attack complex (MAC)-mediated arm of complement, is critical to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice."
In other words, mice bred to be unable to produce complement did not develop osteoarthritis. They also observed that complement is required for joint tissue to become inflamed even after it is mechanically damaged:
"Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints of C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes."
They also found that MAC, another complement effector, plays an important role:
"We next determined whether the MAC-mediated effector arm of the complement cascade is important in osteoarthritis. We found that mice deficient in C6, an integral component of the MAC, were protected against the development of osteoarthritis and synovitis induced by medial meniscectomy. Conversely, mice deficient in CD59a, an inhibitor of MAC6, developed more severe osteoarthritis and synovitis."
Similar phenomena were observed in human tissues:
"Furthermore, MAC co-localized with matrix metalloprotease (MMP)-13 and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints plays a critical role in the pathogenesis of osteoarthritis."
Furthermore, in this excellent study the authors also demonstrated that osteoarthritis features a loss of immune tolerance for breakdown products of joint tissue:
"Products of dysregulated cartilage remodeling and repair may contribute to joint inflammation in osteoarthritis. We examined the ability of osteoarthritic cartilage or specific components of the extracellular matrix (ECM) of cartilage to activate complement in vitro. Pulverized osteoarthritic cartilage induced the formation of C5b-9, as did the ECM components fibromodulin and aggrecan..."
The authors conclude:
"Here we show that the complement cascade is crucial to the pathogenesis of osteoarthritis. Cartilage ECM components released by or exposed in osteoarthritic cartilage may trigger the complement cascade. Additionally, dysregulation of gene expression in joint tissues may contribute to a local preponderance of complement effectors over inhibitors in osteoarthritis, permitting complement activation to proceed unchecked. Complement activation in turn results in the formation of MAC on chondrocytes, which either kills the cells or causes them to produce matrix-degrading enzymes, inflammatory mediators, and further complement effectors—all of which promote joint pathology. Our findings indicate that dysregulation of complement in synovial joints plays a critical role in the pathogenesis of osteoarthritis."
Clinicians should bear in mind their closing statement:
"Recent findings suggest that low-grade complement activation contributes to the development of other degenerative diseases, such as age-related macular degeneration and Alzheimer’s disease. We propose that osteoarthritis can be added to this list of diseases. Our findings provide rationale for targeting the complement system as a disease-modifying therapy for osteoarthritis."
Clinical key point: Joint and connective tissue disorders are almost always a combination of biomechanical factors that determine the location of the pain, and the inflammatory component—often a dysregulated immune system—that determines the character and chronicity of the pain. Practitioners must examine both aspects to design a comprehensive treatment plan.Readers may wish to scrutinize the full text of this excellent paper available here through NIH Public Access. A fine review was also just published in Science.