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Protein | Role | Comments |
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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 |
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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] | |
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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] | |
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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] | |
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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 |
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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] | |
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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 |
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TGFβ | (i) Osteophyte formation [76] | |
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VEGF | (i) Promotes angiogenesis and MMP production [14] | |
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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] | |
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