Table I.
Summary of molecular mechanism of fibroblastic synoviocytes (proliferation and apoptosis).
| Molecules | Mode of action | Species | Dose | Ref | |
|---|---|---|---|---|---|
| In vivo | In vitro | ||||
| Endogenous factors | |||||
| LIGHT | Enhanced the proliferation of FLS, expression of ICAM-1, MCP-1, IL-8, MIP-1α, and NF-κB translocation | RA-FLS | 10 ng/ml | 20 | |
| APRIL | Produced IL-6, TNF-α, IL-1β, and enhanced FLS proliferation | RA-FLS, Rat adjuvant-induced arthritis (AA) model | 30 to 300 ng/ml | 21,22 | |
| Shh signalling | Mediated the proliferation and migration through MAPK/ERK pathway | RA-FLS | 1, 10 μΜ | 23 | |
| GPI | Stimulated the secretion of TNF-α and IL-1β | RA-FLS, arthritic synovial tissues from RA patients | 1 to 10 μg/ml | 24 | |
| Survivin | Promoted proliferation | RA-FLS | 25 | ||
| JMJD3 | Activated proliferation and migration | RA-FLS, CIA mice | 26 | ||
| CYLD | Enhanced cell growth and cytokine production | RA-FLS | 27 | ||
| RasGRPs | Enhanced cell motility and IL-6 production | RA-FLS, CIA mice | 28 | ||
| TGF-β1 | Activated NF-κB, AP-1, migration, and invasion | RA-FLS, SF from RA patients | 1 to 100 ng/ml | 29,30 | |
| SAA | Promoted migration, angiogenesis through MMP-2/9, activation of NF-κB, and cytokine production | RA-FLS, RA synovial/SCID mouse | 50 μg/ml | 10 to 50 μg/ml | 31,32 |
| DLL-1 | Suppressed IL-6 and MMP-3 | 33 | |||
| Calreticulin | Induced Bcl-xL, Mcl-1 through PI3K/Akt and STAT3 pathways | RA-FLS | 34 | ||
| Cytokines | |||||
| LTα | Activation of MAPK, ERK1/2, p38, PI3K/Akt pathway, NF-κB translocation, IL-6/8, and MMP-3 | RA-FLS | 0.5 nM | 35 | |
| IL-21 | Stimulated the proliferation and secretion of TNF-α and IL-6 through ERK1/2, PI3K/Akt, and STAT3 | RA-FLS | 1 to 100 ng/ml | 36 | |
| IL-32γ | Enhanced expression of IL-6 and IL-8 through activation of ERK1/2 | RA-FLS | 50 to 100 ng/ml | 37 | |
| IL-27 | Induced expression of adhesion molecules, inflammatory cytokines, and activated inflammatory signalling pathways | RA-FLS | 10 to 100 ng/ml | 38 | |
| IL-36α | Activated p38 MAPK signalling and pro-inflammatory cytokines | RA/Murine FLS, IL-36R-deficient FLS | 39 | ||
| Synthetic compounds | |||||
| C43 | Inhibited proliferation, inflammation, and bone injury | RA-FLS, SIA mice, and CIA mice | 6 to 30 mg/kg | 30 μM | 40,41 |
| ATO | Induced apoptosis through caspase signalling | RA-FLS, CIA rats | 1 to 6 mg/kg | 0.1 to 8 μM | 42,43 |
| DMHP | Induced apoptosis through enhancing BAX and caspase-3 | RA-FLS, AA rats | 20 to 150 mg/kg | 2.5 to 20 μM | 44 |
| NCL | Reduced E-selectin, ICAM-1, and VCAM-1 and inhibited migration and invasion | RA-FLS, RA patients | 1,000 mg/day | 20 to 100 nmol/l | 45,46 |
| SAHA | Induced apoptosis through enhancing caspase-3 and ROS | RA-FLS | 5 μM | 47 | |
| Natural compounds | |||||
| Resveratrol | Mediated apoptosis and inhibited IL-1β, MMP-3, and phosphorylated Akt | RA-FLS, RA patients | 1 g/person | 6.25 to 50 μM | 48,49 |
| Hesperidin | Down-regulated TNF-α and reduced MMPs | RA-FLS, AIA and CIA mice | 20 to 150 mg/kg | 2.5 to 20 μM | 50,51 |
| MMC | Induced apoptosis through ROS production | RA-FLS | 10 to 100 μg/ml | 52 | |
| Quercetin | Enhanced apoptosis through inhibition of PI3K/Akt pathway | RA-FLS | 200 μM | 53 | |
APRIL, A proliferation-inducing ligand; ATO, arsenic trioxide; Bcl-xL, B-cell lymphoma-extra large; C43, compound 43; CYLD, cylindromatosis; DLL-1, delta like canonical notch ligand 1; DMHP, 7,3'-dimethoxy hesperetin; ERK1/2, extracellular signal‑regulated protein kinase 1/2; GPI, glucose 6-phosphate isomerase; IL-21, interleukin-21; IL-27, interleukin-27; IL-32γ, interleukin-32γ; IL-36α, interleukin-36α; JMJD3, Jumonji C family of histone demethylases; LIGHT, lymphotoxin-like herpes simplex virus glycoprotein D, a receptor expressed by T lymphocytes; LTα, lymphotoxin α; Mcl-1, myeloid cell leukemia-1; MMC, mitomycin C; NCL, niclosamide; RasGRPs, Ras guanine nucleotide-releasing proteins; Ref, reference; SAA, serum amyloid A; SAHA, suberoylanilide hydroxamic acid; Shh signaling, Sonic hedgehog signaling; STAT3, signal transducer and activator of transcription 3; TGF-β1, transforming growth factor-β1.