Inhibition of the complement system component C5 as possible treatment in OA

An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

“…In addition to a potential role in PTOA development, several groups have also shown that the complement cascade is involved in the pathogenesis of both early and late-stage OA in the knee [ 36 , 47 , 48 , 49 , 50 , 51 , 52 ]. C3a and sTCC were significantly higher in the SF from patients with early-stage knee OA (having symptoms less than 1 year) compared to healthy individuals [ 49 , 51 ] and complement transcripts and/or activation components C3/C3a, C4a, C4d, C3bBbP, factor B, and sTCC have been detected at high levels in the SF, synovial membrane and in the cartilage of patients with OA in the knee joint [ 36 , 47 , 48 , 49 , 53 ].…”

“…C3a and sTCC were significantly higher in the SF from patients with early-stage knee OA (having symptoms less than 1 year) compared to healthy individuals [ 49 , 51 ] and complement transcripts and/or activation components C3/C3a, C4a, C4d, C3bBbP, factor B, and sTCC have been detected at high levels in the SF, synovial membrane and in the cartilage of patients with OA in the knee joint [ 36 , 47 , 48 , 49 , 53 ]. Recent evidence suggests that all three complement pathways are capable of being activated within the knee joint in both early and late knee OA and that the synovial membrane is the main source of complement activation rather than the articular cartilage tissue [ 50 ]. Patients with OA also exhibited high concentrations of lectin complement pathway components, including mannose bindin lectin (MBL), H-ficolin, M-ficolin, mannan-binding lectin serine protease- 2 (MASP-2), and MASP-3, which were higher in the plasma than the SF [ 54 ], and while the levels were significantly lower than patients with RA, this data suggests a possible role of the lectin pathway in promoting chronic disease in knee OA.…”

Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches

“…Considering that complement appears to play a role in PTOA progression in the knee [ 3 , 207 , 232 , 233 , 234 , 236 , 237 ], there are surprisingly few OA or PTOA studies that have clinically investigated local inhibition of the complement system. At present, there are two complement-inhibiting products that are clinically available.…”

“…The first is a C1 inhibitor (C1INH) and the second, a monoclonal antibody against C5 (Eculizumab, sold under the name Soliris ® ) that inhibits cleavage of C5 into C5a and C5b and thereby prevents the formation of the MAC or TCC. The C1INH was tested in ischemia-reperfusion mediated injuries, while Eculizumab was tested in other inflammatory diseases and was proposed for treatment of rheumatic diseases such as RA or systemic lupus erythematosus (SLE) [ 237 , 238 , 239 ].…”

“…From the few studies that have used complement inhibitors, evidence suggests that they may potentially provide beneficial effects in PTOA [ 45 , 233 , 237 , 240 , 241 ]. Wang et al was the first to investigate the importance of the complement system in OA progression and showed that 5 months after knee joint injury (medial meniscectomy), C5-deficient mice, which are incapable of forming the terminal MAC, were protected against degenerative effects and chondrocytes expressed significantly lower mRNA concentrations of leukocyte chemoattractants, MMPs (-3, 13, and 14) and ADAMTS-4 and -5, likely due to a lack of MAC-mediated signaling when compared to wildtype injured mice.…”