Table 3 Inflammation-related signal pathways in the progression of OA
Pathway | Related genes | Inflammatory mediators | Sites of functions | Pathological mechanisms | Refs. |
|---|---|---|---|---|---|
AMPK pathway | ERK1/2 | IL-1β, IL-6, LIF, MMP-1 MMP-3, MMP-13, ADAMTS-4, PGE2, NO | Cartilage | Downregulating of type II collagen and aggrecan gene expression, enhancing catabolism, reducing cartilage extracellular matrix (ECM) production in chondrocytes | |
P38 | IL-1β, IL-6, MMP-1, MMP-13, ADAMTS-4, PGE2, NO | Cartilage | Enhancing catabolism, reducing cartilage extracellular matrix (ECM) production in chondrocytes | ||
JNK | IL-1β, IL-6, MMP-1, MMP-13, ADAMTS-4, ADAMTS-5, VEGF | Cartilage | Enhancing catabolism, reducing cartilage extracellular matrix (ECM) production in chondrocytes | ||
AMPKα | IL-1β, TNF-α, MMP-3, MMP-13 | Cartilage | Enhancing cartilage catabolism and promoting chondrocyte apoptosis | ||
c-Fos/AP-1 | c-Fos/AP-1 | IL-1β, IL-6, | Cartilage Osteophyte | Enhancing cartilage destruction and osteophyte formation | [156] |
Focal adhesion pathway | FAK | IL-1β, IL-6, IL-8, TNF-α, COX-2 | Cartilage subchondral bone | Enhancing subchondral bone deterioration and cartilage degeneration | |
Hic-5 | IL-1β, TNF-α, MMP-13, ADAMTS-5 | Cartilage | Enhancing cartilage catabolism | ||
Integrinα5β1 | IL-1β, TNF-α, MMP-1, MMP-2, MMP-3, MMP-10, MMP-13, PGE2, NO, ADAMTS-5 | Cartilage | Decreased proliferation of cartilage producing cells, chondrodysplasia, disorganized articular cartilage, and growth plate abnormalities | ||
FoxO3A | FoxO3A | IL-1β, TNF-α, MMP-3, MMP-13, iNOS | Cartilage | Inhibiting the progression of cartilage damage | |
FGF pathway | FGF2 | IL-1β, IL-6, IL-8, TNF-α, MMP-9, MMP-13, MCP-1, CCL2, ADAMTS-5 | Cartilage | Promoting matrix degradation, anti-anabolism, and catabolism, enhancing cartilage destruction | |
HIFs pathway | HIF-1α | IL-1β, IL-6, TNF-α, MMP-13, ADAMTS-5, iNOS, VEGF, PGE2, NOS | Cartilage Synovium | Potentiating the synthesis of ECM, preventing cartilage degeneration | |
HIF-2α | IL-1β, IL-6 MMP-1, MMP-3, MMP-9, MMP-12, MMP-13, ADAMTS-4, NOS2, COX2 | Cartilage | Enhancing cartilage destruction | ||
Hippo-YAP | YAP | IL-1β, TNF-α, MMP-3, MMP-13, ADAMTS-4, ADAMTS-5 | Cartilage | Attenuating cartilage destruction | |
JAK/STAT pathway | JAK/STAT | IL-1β, TNF-α, IL-4, IL-6, IL-10, IL-12, IL-13, IL-23, MMP-1, MMP-3, MMP13, ADAMTS-4, ADAMTS-5 | Cartilage | Promoting ECM degradation and reducing type II collagen expression in chondrocytes | |
mTOR pathway | mTOR | IL-1β, IL-6, TNF-α, MMP-3, MMP-9, MMP-13, COX-2, iNOs, ADAMTS-5 | Cartilage subchondral bone Synovium | Enhancing osteophyte formation, subchondral sclerosis, osteophyte formation and synovial inflammation Enhancing autophagy and inhibiting the apoptosis of chondrocytes | |
NF-κB pathway | RelA/p65 | IL-1β, IL-6, TNF-α, MMP-1, ADAMTS-5, NOS2, COX2 | Cartilage synovium | Enhancing cartilage degradation, aggrecan loss, and cartilage erosion | |
NF-кB1/ p105p50 | IL-1β, IL-6, TNF-α | Cartilage | Enhancing cartilage degradation, aggrecan loss, and cartilage erosion | ||
IκB | IL-1β, IL-6, MMP-13 | Cartilage Synovium | Enhancing cartilage catabolism | ||
IKKα/β | IL-1, NOS2, COX2, MMP-13, ADAMTS-5 | Cartilage | Inhibiting IKK activity significantly, preventing IKB phosphorylation, enhancing chondrocyte catabolism and cartilage degeneration | ||
NFκB/PI3K/AKT | IL-1β, IL-6, TNF-α, MMP-1, MMP-13, ADAMTS-5, NO, PGE2 | Cartilage | Enhancing cartilage catabolism and degeneration | ||
NF-κB/ELF3 | IL-1β, IL-6, TNF-α, LPS, COX2, iNOS, MMP-13 | Cartilage | Inducing the expression of matrix-degrading enzymes, regulating chondrocyte catabolism, enhancing cartilage degradation | ||
NF-κB/Notch1 | IL-1β, IL-6, IL- 8, TNF- α | Cartilage | Impaired synthesis of cartilage-specific extracellular matrix, enhancing cartilage catabolism | ||
PPAR | PPARα/γ | IL-1β, TNF-α, MMP-1, MMP-3, MMP-9, MMP-13, AGEs, NO, PGE2 | Cartilage Synovium | Inhibiting catabolism and inflammatory-related factors, attenuating cartilage damage | |
PGC-1α | PGC-1α | IL-1β, IL-8, TNF-α, MMP-13, COX-2 | Cartilage | Regulating the metabolic abnormalities, inhibiting chondrocyte apoptosis | |
SIRT | SIRT1 | IL-1β, TNF- α, MMP-13, ADAMTS-5 | Cartilage | Inhibiting catabolism | |
SIRT3 | IL-1β, TNF- α MMP-3, MMP-13, COX2, iNOS | Cartilage | Inhibiting inflammation and apoptosis, preventing cartilage damage | ||
SIRT6 | IL-1β, IL-4, IL-8, TNF-α, MMP-2, MMP-9, COX2, PAI-1 | Cartilage Synovium | Inhibiting ECM degradation, preventing cartilage damage | ||
TAK1 | TAK1 | IL-1β, IL-6, TNF-α, MMP-1 MMP-3, MMP-13, VEGF, COX-2, PGE2 | Cartilage Synovium | Enhancing cartilage destruction, synovial inflammation | |
TGFβ /BMP | BMP2 | IL-1, TNF- α, MMP-13 | Cartilage | Inhibiting cartilage degeneration | |
BMP7 | IL-1, IL-6, IL-10, MMP-1, MMP-13 | Cartilage | Inhibiting cartilage degeneration | ||
TGFβs | IL-1, IL-6, TNF- α MMP-3, MMP-9, MMP-13, ADAMTS-5 | Cartilage | Counteracting the suppression of proteoglycan synthesis | ||
TLRs | TLRs | IL-1β, TNF-α, IL-6,IL-8, IL-12, IL-17, CCL5, NO | Cartilage | Increasing the shift from anabolism to a catabolism, enhancing cartilage degradation | |
Wnt pathway | β-catenin | IL-1β, IL-6, TNF-α MMP-1, MMP-3, MMP-13, ADAMTS-5 | Cartilage | Enhancing cartilage degradation | [217] |
|  | Wnt-3A | IL-1β, MMP-1, MMP-3, MMP-13 | Cartilage | Attenuating catabolism | |
|  | Wnt-5A | IL-1β, MMP-1, MMP-3, MMP-9, MMP-13 | Cartilage | Anti-anabolic and enhancing catabolism, inhibiting type II collagen | |
|  | Wnt-7A/β-catenin | IL-1β, MMP-1, MMP-3, MMP-13 | Cartilage | Inhibiting type II collagen | |
|  | Wnt-7B/β-catenin | IL-1β, IL-6, TNF-α, MMP-1, MMP-3, MMP-13 | Cartilage | Enhancing cartilage destruction |