Table 3.
Cartilage ECM components and chondrocyte cell surface proteins interacting with complement factors.
| ECM component | Normal function | Interaction with complement | Reference |
|---|---|---|---|
| Type II collagen | Specific and major collagen type in cartilage ECM | (+) Formation of collagen-antibody immune complexes in cartilage and subsequent complement activation via classical pathway | Koobkokkruad et al118 |
| Type IX collagen | Specific collagen type in cartilage ECM | (−) NC4 domain of collagen IX inhibits complement directly due to attenuation of MAC formation and indirectly through binding and enhancing activity of complement inhibitors, C4B-binding protein, and factor H | Kalchishkova et al119 |
| Aggrecan | Specific and major proteoglycan in cartilage ECM | (+) The C-type lectin of the aggrecan G3 domain activates complement | Wang et al8, Furst et al99 |
| GAGs, eg, CS | Major component of aggrecan | (+) Factor H provides binding sites for GAGs (−) Complement factors, such as CFB, C1s, C3, and C1r, were decreased by CS |
Li et al140, Clark et al117, Calamia et al107 |
| Hyaluronan | Attached to aggrecan | (−) A case was reported where an induction of anaphylatoxin C5a and TCC led to joint inflammation in response to multiple intra-articular injections of hylan G-F 20 | Sofat97, Dragomir et al105 |
| COMP | Mediates collagen fibrillogenesis | (+) COMP induces activation and deposition of C3b and C9 via the alternative pathway in RA (−) COMP inhibits the classical and the lectin pathways due to direct interaction with the stalk region of C1q and mannose-binding lectin in RA Both could not be shown in OA by Happonen et al100 |
Blom23, Happonen et al100,141 |
| Fibronectin and its fragments | Fibronectin regulates cell differentiation, adhesion, and migration | (Effects not shown) binding to the C1q component of complement | Barilla et al142, Casons et al143 |
| Biglycan and decorin (SLRP) | Decorin: limits collagen fiber formation, regulates TGF-β functions | (−) Decorin and biglycan: bind to C1q, can inhibit classical pathway, biglycan: inhibits also lectin pathway | Groeneweld et al110, Krumdieck et al111 |
| Fibromodulin (SLRP) | Keratan sulfate PG, bound to collagen fiber surface: limits collagen fiber formation | (+) Activates complement by binding to C1q, interaction with factor H | Wang et al8, Sofat97, Sjoberg et al98 |
| Chondroadherin and osteoadherin (SLRP) | Cell-matrix interaction binds to collagens and α2β1 integrin | (+) Activates complement by binding to C1q, interaction with factor H | Sjoberg et al112 |
| DAMP, damage-associated molecular patterns | Cartilage ECM or cellular fragments arising during OA-associated tissue disintegration | (+) A subgroup of DAMPs acts as neoantigens and exerts complement activation | Liu-Bryan6, Land144 |
| Integrins and TLR | Integrins: important cell-ECM receptors regulating diverse cellular processes TLR: besides recognizing patterns of microbial origin and activating innate immunity, they can also bind to various DAMPs, fibronectin, hyaluronan, and biglycan fragments |
(Effect not shown) α2β1 integrin Interacted with C1q Direct interaction between TLR and C5a/C5aR signaling, shown in immune cells |
Hajishengallis and Lambris145, Holst et al146, Sillat et al147, Zutter and Edelson148 |
Abbreviations: COMP, cartilage oligomeric protein; CS, chondroitin sulfate; DAMP, damage-associated molecular pattern; ECM, extracellular cartilage matrix; GAGs, glycosaminoglycans; OA, osteoarthritis; RA, rheumatoid arthritis; SLRP, small leucine-rich repeat protein; TGF-β, transforming growth factor β; TLR, toll-like receptor.