Table 2: Role of dominant effectors involved in OA pathogenesis.


IL-1β(i) Produced by macrophages [29]
(ii) Receptors upregulated in OA chondrocytes and fibroblasts [84]
(iii) Stimulates production of MMPs [85], ADAMTS-4 [86], and chemokines [87]
(iv) Inhibits proteoglycan and type II collagen via repressing GlcAT-1 [88]
(v) Induces apoptosis in chondrocytes via upregulation of Bcl-2 family of proteins, mitochondrial depolarization [89], and perhaps ROS [90] and NO production [91]
(i) GlcAT-1 is an important enzyme for production of glycosaminoglycan

TNFα(i) Produced by macrophages [29]
(ii) Promotes resorption and inhibits production of proteoglycan in cartilage [30]
(iii) Stimulates MMP and chemokine production [32]
(iv) Decreases collagen production [32]
(v) May form a negative feedback loop with HNP1-3 [25]

IL-6(i) Produced by fibroblasts [14], chondrocytes [92, 93], and B cells [83]
(ii) Production by chondrocytes induced by PGE2 [92], TNFα, and IL-1β [93]
(iii) Found to be present in intimal layer and produced mostly by plasma cells when detected in high levels (>600 pg/mL) in synovial fluid [83]
(iv) Activates JAK/STAT to inhibit aggrecan core and link protein and type II collagen gene expression; blocking STAT phosphorylation inhibits this downregulation [94]
(v) After binding to its receptor, it binds and inactivates transcription factor for COL2A1 gene, which encodes procollagen chain of triple helix of type II collagen [95]
(vi) Upregulates expression of MMPs in conjunction with IL-1 [96]

Complement(i) Expression and activation abnormally high in OA synovium, significantly in early OA [17]
(ii) MAC present around chondrocytes and in synovium in late OA [17]
(iii) MAC stimulates MMP, ADAMTS, and chemokine production in chondrocytes [17]
(iv) Cartilage ECM, fibromodulin, and aggrecan induced formation of C5b-9 [17]
(v) C5 knockout mice showed no significant synovitis or cartilage loss versus control C5+ mice 8–12 weeks s/p medial meniscectomy [17]
(vi) C6 mice developed roughly half the degeneration from synovitis as C6+ mice s/p medial meniscectomy [17]
(vii) CD59 mice developed more severe OA [17]
(viii) C1s cleaves IGFBP-5 which is chondroprotective [18]
(ix) C1s inhibition shown to promote better joint architecture in dogs [18]

TLR (i) Activated by DAMPs released from ECM in joint damage [14]
(ii) Induce proinflammatory cytokine production (IL-1β, TNFα, MMP, etc.) by macrophages [14]
(iii) Induce catabolic pathways in chondrocytes [15]
(iv) Upregulated on chondrocytes in advanced OA [15]
(v) TLR4 on OA chondrocytes more sensitive to S100 than control [16]
(i) S100 is a DAMP

PGE2(i) Upregulated in OA joints [92]
(ii) Inhibits proteoglycan synthesis by suppressing aggrecan gene transcription [92]
(iii) EP2,4 receptors upregulated in joint cartilage as OA progresses [92]
(iv) Decreases collagen type II/type I ratio [92]
(v) When coupled with IL-1 stimulation, it greatly increases expression of IL-6 and iNOs [92]

ADAMTS(i) ADAMTS-4 can be downregulated by inhibiting TNFα and/or IL-1β while ADAMTS-5 is constitutive in human [29](i) Uncertainty over which of the two is more significant in OA pathogenesis

TGFβ(i) Osteophyte formation [76]

VEGF(i) Promotes angiogenesis and MMP production [14]

IL-4,7,8,10,13,15,17,18, adipokines, and leukemia inhibitory factor(i) Detected in synovium [5]
(ii) IL-17 works synergistically with TNFα and IL-1 and is released by mast cells [97]
(iii) Increased levels of IL-15 in early versus late OA [66]