Table 1.

Innate immunity in OA

Innate immune players	Agonists or DAMPs implicated	Significance (in vivo testing)
Complement: C5, C6, MAC (C5b-9)	COMP Fibromodulin Aggrecan	C3 knockout: No chondroprotection in the medial meniscectomy model [41••] C5, C6 knockout (disruption of MAC formation): Decreased OA in the medial meniscectomy model [41••] CD59 (the MAC inhibitor) knockout: Increased OA in the medial meniscectomy, DMM and spontaneous aging models [41••]
PRRs: TLRs, RAGE, sCD14, NLRP3	S100A8/A9 (TLR4, RAGE), S100A4 and S100A11 (RAGE) S100A12 (RAGE) HMGB1 (TLR2, TLR4, RAGE) TN-C (TLR4) LMW-HA (TLR2, TLR4) Plasma proteins from OA SF (TLR4) AGEs (RAGE) Hydroxyapatite (TLR4, NLRP3) CPPD (TLR2, NLRP3) Other potential candidates (not reviewed): Biglycan (TLR2, TLR4) Necrotic cell debris, oxidized phospholipids (TLR2, TLR4) HSPs (e.g., Hsp96) (TLR2, TLR4) Fn extra domain A (TLR4)	S100A9-knockout: Decreased OA in the collagenase- induced model [30] TN-C knockout: Increased OA in the ACL and MCL transection model [28] TLR2 knockout: Increased OA in the collagenase-induced model; no significant effect in the DMM model [29] TLR2/TLR4 double knockout: Mild chondroprotection in the meniscectomy model (Liu-Bryan, unpublished data) RAGE knockout: No chondroprotection in the ACL transection model [31] Increased SF sCD14: Seen in early and advanced human OA [36] Knockout of NLRP3 in ANK-deficient mice: Less joint inflammation and cartilage degeneration [54•]

ACL anterior cruciate ligament, AGEs advanced glycation-end products, COMP cartilage oligomeric matrix protein, CPPD calcium pyrophosphate dihydrate, DMM destabilization of the medial meniscus, Fn fibronectin, HA hyaluronan, HSP heat shock protein, LMW low molecular weight, MAC membrane attack complex, MCL medial collateral ligament, NLRP3 NACHT LRR and PYD domains-containing protein 3, PPRs pattern recognition receptors, RAGE receptor for AGEs, sCD14 soluble CD14, SF synovial fluid, TLR toll-like receptor, TN-C tenascin-C