Osteoarthritis and the Complement Cascade

Abstract

Accumulating evidence demonstrates that complement activation is involved in the pathogenesis of osteoarthritis (OA). However, the intimate complement regulation and cross talk with other signaling pathways in joint-associated tissues remain incompletely understood. Recent insights are summarized and discussed here, to put together a more comprehensive picture of complement involvement in OA pathogenesis. Complement is regulated by several catabolic and inflammatory mediators playing a key role in OA. It seems to be involved in many processes observed during OA development and progression, such as extracellular cartilage matrix (ECM) degradation, chondrocyte and synoviocyte inflammatory responses, cell lysis, synovitis, disbalanced bone remodeling, osteophyte formation, and stem cell recruitment, as well as cartilage angiogenesis. In reverse, complement can be activated by various ECM components and their cleavage products, which are released during OA-associated cartilage degradation. There are, however, some other cartilage ECM components that can inhibit complement, underlining the diverse effects of ECM on the complement activation. It is hypothesized that complement might also be directly activated by mechanical stress, thereby contributing to OA. The question arises whether keeping the complement activation in balance could represent a future therapeutic strategy in OA treatment and in the prevention of its progression.

Metabolomic and Proteomic Stratification of Equine Osteoarthritis

“…However, a growing body of evidence has identified a role of complement activation within OA pathogenesis, which is further supported by this study (120). Complement has been identified to have a role in the degradation of cartilage ECM, synovitis and osteophyte formation, with complement split fragment C3a found to upregulate gene expression of tumour necrosis factor-α and Interleukin-1β, pro-inflammatory cytokines central to OA pathogenesis (97,120).…”

“…Additionally, the uncharacterised protein F6ZR63, the second most important variable of influence driving the biobank Lasso model, was found to have a high level of amino acid sequence similarity to complement factor H-like isoform X1. The complement system is an important component of the innate immune response, encompassing various roles including opsonisation initiation, pathogen phagocytosis, the inflammatory response and terminating within cell lysis (120,121). However, a growing body of evidence has identified a role of complement activation within OA pathogenesis, which is further supported by this study (120).…”

“…The complement system is an important component of the innate immune response, encompassing various roles including opsonisation initiation, pathogen phagocytosis, the inflammatory response and terminating within cell lysis (120,121). However, a growing body of evidence has identified a role of complement activation within OA pathogenesis, which is further supported by this study (120). Complement has been identified to have a role in the degradation of cartilage ECM, synovitis and osteophyte formation, with complement split fragment C3a found to upregulate gene expression of tumour necrosis factor-α and Interleukin-1β, pro-inflammatory cytokines central to OA pathogenesis (97,120).…”

Characterization of the Interleukin-17 Effect on Articular Cartilage in a Translational Model. An Explorative Study

“…Other immune response mediators -complement factor B and SAA were also upregulated in IL-17Atreated explant conditioned media. Complement has a role in OA and factor B synthesis has been previously shown to be regulated by IL-17 in fibroblasts (57)(58)(59)(60). Struglics et al (2016) CHI3L1 (YKL-40), which was upregulated in the conditioned media of our IL-17A explant group, is also involved in joint pathology -its elevation in synovial fluid independently and positively related to WOMAC pain (r = 0.531, p = 0.001), physical disability (r = 0.380, p = 0.025), and total scores (r = 0.407, p = 0.01) in knee OA patients (62).…”

Matrix-targeted Nanoparticles for MMP13 RNA Interference Blocks Post-Traumatic Osteoarthritis

“…OA-relevant PTGS2 (prostaglandin-endoperoxide 16 synthase 2, an inflammation driver that encodes the cyclooxygenase 2 enzyme (COX2) and IL1RN 17 encoding the interleukin 1 receptor antagonist protein (IL1RaP) in which its knock-out correlates 18 with spontaneous arthritis development (65) were, for example, significantly reduced in 19 mechanically loaded joints with mAbCII-siNP delivery of siMMP13 versus siNEG. Coupled with 20 reduction of innate immune response, MMP13 silencing also reduced expression of several serine 21 proteases (C1S, C1RA, and C2) that are components of the complement pathway, which is known 22 to be associated with OA progression (66,67). The local reduction in these components indicates 23 reduced number or activation of circulating monocytes, macrophages, and monocyte-derived 1 dendritic cells that all express C1s, C1RA, and C2 (68).…”