Table 4. Characteristics of in vitro studies about the effect of pomegranate on osteoarthritis .
| Author (date) | Population | Intervention | Dose | Duration | Findings | Reference |
| Yang et al (2021) | TNF-α and IL-1β-induced chondrocytes as a model of OA | Punicalin | 0-100 μg/mL | 24 Hours | (1) Protection against growth inhibition of chondrocytes and impeding chondrocyte apoptosis (2) Blocking phosphorylation and cytoplasmic transfer of FOXO3 protein level (3) Decrease MMP-9, COL10A1, Runx2, IHH, and PTHLH mRNA expression (4) Up-regulation of Sox-9 and COL2A1 mRNA expression (5) No change in COL9A1, MMP-13, Runx3 mRNA expression |
47 |
| Lin et al (2020) | Human OA chondrocytes | Ellagic acid | 12.5, 25, 50 μM | 24 Hours | (1) Inhibition of IL-1β-induced expression of iNOS and COX-2 in a dose-dependent manner (2) Decrease in IL-1β-induced NO, PGE2, IL-6, and TNF-α production in a dose-dependent manner (3) Suppression of ADAMTS-5 and MMP-13 generation in a dose-dependent manner (4) Inhibition of IL-1β-stimulated cytoplasmic collagen II degradation (5) Amelioration of the deterioration of ECM (6) Up-regulation of the expression of collagen-II and aggrecan in a dose-dependent manner (7) Reversing protein expression of IkBα in the cytoplasm in a dose-dependent manner (8) Inhibition of the translocation of p65 into the nucleus in a dose-dependent manner (9) Suppression the activation of the NF-kB pathway in a dose-dependent manner |
25 |
| Ding et al. (2020) | IL-1β-induced rat chondrocytes as a model of OA | Urolithin A | 1, 7.5, 15 μM | 48 hours | (1) Suppression of the IL-1β-induced overproduction of MMP-9 and ADAMTS4 mRNA in a dose-dependent manner (2) Marked amelioration of IL-1β-induced degradation of cartilage matrix in a dose-dependent manner (3) Reversing downregulated gene expression of collagen II in IL-1β stimulated condition in a dose-dependent manner (4) Reducion in protein expression of MMP-3 and MMP-13 (5) Suppression of IL-1β-induced expression of iNOS and COX2 in a dose-dependent manner (6) Prevention of IL-1β-induced degradation of Sox-9, collagen II, and Aggrecan in a dose-dependent manner (7) Suppression of the upregulated phosphorylation of MAPK pathway members such as ERK1/2, JNK, and p38 in a concentration-dependent manner (8) Inhibition of IL-1β-induced NF-κB activation in a dose-dependent manner |
33 |
| Kong et al (2020) | TBHP-treated chondrocytes as a model of OA | Punicalagin | up to 50 μg/mL | 24-48 hours | (1) Increase in HO-1, SOD1 and NQO1 proteins expression (2) Increase in Bcl2 levels (3) Decrease in Bax levels (4) Cleavage of caspase-3 and decrease in immunofluorescence intensity of cleaved caspase-3 (5) Attenuation of TBHP-Induced oxidative stress and apoptosis (6) Inhibition of ADAMTS-5, MMP-3, and MMP-13 expression (7) Enhancement of intensity of type II collagen (8) Inhibiting ECM degradation (9) Leading to smooth, richer proteoglycan and hypercellularity cartilage surface and a lower OARSI score (10) Enhancement of the state of autophagy and ameliorating dysfunctional autophagic flux |
24 |
| Fu et al (2019) | Primary human OA chondrocytes | Urolithin A | 3, 10, or 30 μM | 24 Hours | (1) Inhibition of up-regulation of IL-1β-induced mRNA and protein expression of iNOS and COX-2 in a dose-dependent manner (2) Decrease in NO generation and PGE2 expression in a dose dependent manner (3) Inhibition of TNF-α and IL-6 production in a concentration-dependent manner (4) Opposing the stimulatory effect of IL-1β on ADAMTS-5 and MMP-13 expression in a dose-dependent manner (5) Reversing the inhibitory effect of IL-1β on aggrecan and collagen-II in a dose-dependent manner (6) Suppression of IκBα degradation and p65 translocation in a concentration-dependent manner (7) Inhibition of the expression of the phosphorylation of PI3K and Akt in a concentration-dependent manner |
27 |
| Taherian et al (2018) | LPS-stimulated Bovine Fibroblast-like synoviocytes (BFLS) as a model of OA | Punicic Acid | 1 μg/mL | 24 Hours | (1) Decrease in MMP-9 gene and protein expression and activity of MMP-9 in a concentration-dependent manner (2) No change in MMP-1, MMP-2 or MMP-3 gene and protein expression (3) No change in MMP-2 activity (4) Decrease in synoviocyte cell migration and cell invasion in a concentration-dependent manner |
34 |
| Lee et al (2018) | IL-1β-induced primary rat chondrocytes as a model of OA | POMx (70% acetone extract of pomegranate peels) | 12.5 to 100 μg/mL | 16 Hours | (1) Reduction in iNOS, MMP-13, and COX-2 protein expression in a dose-dependent manner (2) Reduction in IL-1β-induced PGE2 production |
28 |
| Lee et al (2018) | IL-1β-induced primary rat chondrocytes as a model of OA | Punicalagin | 6.25 to 50 μg/mL | 16 Hours | (1) Inhibition of iNOS, MMP-13, and COX-2 protein expression (2) Reduction in IL-1β-induced PGE2 production |
28 |
| Haseeb et al (2017) | Human OA chondrocytes | Pomegranate fruit extract | 50 μg/mL | 2 Hours | (1) Inhibition of IL-1β-induced mRNA and protein expression of IL-6 in a dose dependent manner (2) Suppression of the IL-1β-mediated generation of ROS (3) Inhibition of the IL-1β-induced activation and DNA binding activity of NF-κB/p65 (4) Inhibition of the phosphorylation of IKKα/β and downregulation of the expression of IKKβ at protein and mRNA levels in a dose-dependent manner (5) Inhibition of the intrinsic and IL-1β induced phosphorylation of NIK |
35 |
| Choi et al (2017) | LPS- and rhIL-1α-stimulated rat chondrocytes as a model of OA | Dried pomegranate concentrate powders | 1 mg/mL | 24 Hours | (1) Inhibition of LPS-stimulated PGE2 production and 5-LPO activity (2) Inhibition of rhIL-1α-stimulated MMP-2 and MMP-9 activities (3) Up-regulation of mRNA expressions of ECM related chondrogenic genes such as collagen type II, Sox-9, and aggrecan |
36 |
| Haseeb et al (2013) | Human OA chondrocytes | Delphinidin | 10 and 50 μg/mL | 2 Hours | (1) Inhibition of IL-1β-induced expression of COX-2 mRNA and protein and the production of PGE2 (2) Suppression of IL-1β-induced activation and DNA binding activity of NF-kB p65 (3) Inhibition of IL-1β-induced phosphorylation and degradation of IkBα (4) Down-regulation of the protein and mRNA expressions of IKKβ (5) Inhibition of the activation of a kinase upstream of NIK and IL-1β-induced activation of NF-kB (6) Inhibition of the IL-1β-induced phosphorylation and degradation of IRAK1 |
37 |
| Rasheed et al (2010) | Primary human OA chondrocytes | Pomegranate extract | 6.25 to 100 μg/mL | 2 Hours | (1) Attenuation of the IL-1β-induced phosphorylation of both MKK-3 and MKK-6 in a dose dependent manner (2) Inhibition of IL-1β-induced phosphorylation of p38-MAPK and activation of p38α-MAPK (3) Inhibition of IL-1β-induced increase in the DNA binding activity of RUNX-2 transcription factor in a dose-dependent manner (4) No effect on binding of IL-1β with IL-1R |
38 |
| Ahmed et al (2005) | Human OA chondrocytes | Pomegranate fruit extract | 6.25–50 mg/L | 24 Hours | (1) Blocking the effect of IL-1β on the viability of OA chondrocytes and IL-1β–induced cytotoxic effects (2) Inhibition of the IL-1β-induced upregulation of MMP-1, MMP-3, and MMP-13 mRNA levels (3) Inhibition of the IL-1β-induced production of MMPs 1,3,13 (4) Inhibition of IL-1β–induced OA cartilage degradation (5) Inhibition of the IL-1β-induced phosphorylation of ERK, JNK, p38-MAPK, c-Jun, and ATF-2 (6) Inhibition of the DNA binding activity of NF-κB |
39 |
OA: osteoarthritis; FOXO3: Forkhead box O3; MMP: matrix metalloproteinase; COL10A1: Collagen Type X Alpha 1 Chain; RUNX-2: runt-related transcription factor-2; IHH: Indian Hedgehog Signaling Molecule; PTHLH: Parathyroid Hormone Like Hormone; Sox-9: SRY-box 9; COL2A1: Collagen Type II Alpha 1 Chain; COL9A1: Collagen Type IX Alpha 1 Chain; IL: interleukin; iNOS: inducible nitric oxide synthase; COX-2: cyclooxygenase-2; NO: nitric oxide; PGE2: prostaglandin E2; TNF: tumor necrosis factor; ADAMTS: A Disintegrin and Metalloproteinase with Thrombospondin motifs; ECM: extracellular matrix; IkBα: inhibitor of kappa Bα; NF-κB: nuclear factor kappa B; MAPK: mitogen-activated protein kinase; ERK1/2: extracellular signal-regulated protein kinase; JNK: c-Jun N-terminal Kinase; TBHP: Tert-butyl hydroperoxide solution; HO-1: heme oxygenase-1; SOD: superoxide dismutase; NQO: NAD(P)H quinone dehydrogenase; Bcl-2: B-cell lymphoma-2; OARSI: Osteoarthritis Research Society International; NIK: NF-kB-inducing kinase; IRAK1: IL-1 receptor-associated kinase-1; MKK: MAPK kinase, ATF-2: activated transcription factor-2.