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Osteoarthritis (OA), also known as degenerative joint disease, is mainly characterized by abnormal proliferation of cartilage at the joint margins and cartilage detachment. Clinical manifestations include chronic joint pain, swelling, and friction sounds during activities, which can lead to joint deformity and even loss of the ability to walk in the end stage.

Proteomics and Complement Proteins in OA

Proteomics technology and mass spectrometry have shown that complement proteins are abnormally over-expressed in the synovial fluid of patients with OA. This includes the abnormal increase of C3, C4, and C5 complement proteins. This increase causes complement activation, increased formation of C3 and C5 convertases, and ultimately leads to the increased production of the membrane attack complex (MAC), which promotes joint damage and inflammation.

Inflammation and the Innate Immune System

Studies have indicated that OA involves a lower degree of inflammation mediated by the innate immune system. Analysis of synovial fluid and cell membranes of patients with OA has revealed significantly elevated levels of complement activation fragments and their pro-inflammatory receptors in the synovial membranes. This suggests the complement system plays an important role in tissue damage in OA. Complement activation in the synovial fluid produces various complement components, among which C3 and C5 convertases form MACs that create membrane pore channels in target cells, leading to cell lysis and triggering joint inflammation. Additionally, interaction of complement activation products with chemokines increases bone damage.

The Complement System

The complement system, a primary line of defense of the innate immune system against pathogens, consists of more than 30 proteins involved in heat-resistant protein hydrolysis cascade reactions. These components include complement intrinsic components, factors regulating complement activation, and complement receptors distributed on cell membranes. The complement system plays a role in host defense and adaptive immune regulation by stimulating allergens and B and T lymphocytes. In OA's molecular mechanism, stimulation of host cells activates the complement system, producing C3 and C5 convertases that induce C3a and C5a allergens. These allergens induce inflammatory factor production by immune cells, ultimately leading to OA through the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Reducing arthritis can be achieved by decreasing the production of complement activation products, preventing cell lysis, and alleviating arthritis.

Pathogenesis of OA and Complement System Modulators

Chondrocyte lysis induced by complement system activation is a recognized pathogenesis of OA, followed by a cascade reaction involving serine proteases that result in mediators such as MACs, chemokines, and proinflammatory factors. Complement system-based modulators that inhibit complement system activation are considered a primary goal in OA treatment. The diversity of complement components and effector proteins provides multiple potential targets for interventional therapy. Based on the major components of the MAC leading to cell lysis, complement protein modulators are categorized into:

1. C3 complement protein modulators

2. C4 complement protein modulators

3. C5 complement protein modulators

4. Novel fusion protein complement modulators

Conclusion

Understanding the role of the complement system in the pathogenesis of osteoarthritis highlights potential therapeutic targets for managing this debilitating condition. By focusing on complement system modulators, new treatment strategies may emerge that could better control inflammation and prevent joint damage, ultimately improving the quality of life for patients with OA. Continued research in this area is essential to develop more effective interventions and to fully elucidate the complex mechanisms underlying osteoarthritis.

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