The C-type lectin of the aggrecan G3 domain activates complement

Abstract

Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint.

Osteoarthritis and the Complement Cascade

“…However, the observed complement activation is attenuated due to binding of complement inhibitor FH to CLD and CRP domains. 99 This study therefore suggested aggrecan CLD as one factor involved in the sustained inflammation of the joint. GAG are generally described to have anti-complementary effects.…”

“…Complement activation can be mediated not only by various ECM components, such as fibromodulin, 8,98 aggrecan, 8,99 and cartilage oligomeric matrix protein (COMP) 100 (Table 3), as described in detail below, but also by hydroxyapatite and calcium pyrophosphate dihydrate crystals, by apoptotic cells and the resulting cell debris. 18 Hyaluronan is a major component of the ECM in cartilage and in various tissues.…”

“…Fragments of aggrecan, the most abundant large cartilage-specific PG, released in damaged cartilage can activate the complement system. 99 The aggrecan C-type lectin domain (CLD), a part of the G3 domain, is seen released in articular diseases. They can activate the classical but to a lesser extent also the alternative complement pathway, via binding of C1q and C3, respectively.…”

Roles of larval sea urchin spicule SM50 domains in organic matrix self-assembly and calcium carbonate mineralization

“…Interestingly, C type lectin domains in the genus Strongylocentrotus have been implicated in immunity re sponses and suggest that these domains have been co opted for biomineralization purposes through evolution (Gross et al, 1999;Silva, 2000;Smith, 2005). As is often the case, the C type lectins discussed here require proper amounts of Ca 2+ ions to fold properly for correct structural conformations (Diao and Tajkhorshid, 2008;Fuerst et al, 2013). In contrast, numerous intrinsically disordered repeat (IDP) domains are found in the SMPs and have no such necessity of conformation for proper function.…”

Osteoarthritis and Immunity

“…Apart from this major, evolutionary determined protective function, it also plays a role in the removal of cellular remains and immune complexes, opsonization, and B-and T-lymphocyte stimulation [30]. The cartilage damage products released during joint damage are a separate class of potent complement modulators [31,32,33,34]. Different ECM components and their fragments in the degenerative joints can also active the complement [35,36].…”