Table 2.

Natural-flavonoid-based pharmacology therapy for OA.

Compound (Source)	Category	Structure	Therapeutic Target	Treatment	Ref.
Apigenin (chamomile, thyme, tea, extra virgin oil)	4′,5,7-Trihydroxyflavone		Inhibition of IL-1β-induced effects and NF-κB, Hif-2α, and TGFβ/Smad2/3 pathways in chondrocytes.	Anti-inflammatory effect, prevent cartilage degradation.	[32,33]
			Increases BMP-2, BMP-7, APL, and Col I in osteoblasts. Induces JNK and p38 MAPK pathways in osteoblasts.	Promotes osteoblastic differentiation.	[34,35]
Astragalin (Cuscuta chinensis)	Kaempferol 3-glucoside		Inhibition of IL-1β/NF-κB and MAPK in chondrocytes.	Anti-inflammatory effect, suppresses bone destruction.	[38,39]
Baicalein (Scutellaria baicalensis)	5,6,7-Trihydroxyflavone		Inhibition of IL-1β-induced effects in chondrocytes. Increases secretion of GAG and Col II.	Anti-catabolic and anti-apoptotic effects.	[42,43,44]
			Increases osteoblast differentiation and inhibits osteoclast differentiation.	Attenuated OA in pre-clinical models. Inhibition of bone loss.	[45,46]
Chrysin (Passiflora caerulea, Scutellaria baicalensis)	5,7-Dihydroxyflavone		Inhibition of IL-1β/NF-κB induction. Dowregulates the expression of iNOS, COX-2, MMP-1, MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, and HMGB-1 in chondrocytes. The level of NO, PGE2 decreases.	Anti-inflammatory and anti-apoptotic effects.	[48,49]
			Activation of ERK/MAPK signaling in osteoblasts and upregulation of Runx-2 and Osx.	Induction of osteoblast differentiation.	[50,51]
Genistein (Genista tinctoria)	Isoflavone		Inhibition of IL-1β-induced effects via the activation of Nrf2/HO-1 signaling in chondrocytes.	Anti-catabolic effect. Attenuated OA in pre-clinical models.	[58,59]
			Increases osteoblast differentiation via MAPK activation and inhibits osteoclast differentiation via NF-κB inhibition.	Inhibition of bone loss.	[60,61,62,63]
Icariin (Epimedium)	Flavonoid glycoside		Inhibition of IL-1β/TNF-α/LPS-induced effects via the inhibition of NF-κB and the activation of Nrf2/HO-1 signaling in chondrocytes. Increases the secretion of ACAN and Col II. Decreases the expression of MMP-1, 3, 9, 13, COX-2, and iNOS.	Anti-inflammatory and anti-catabolic effects. Increased cartilage repair in pre-clinical OA models.	[64,65,66,67,68]
			Increases osteoblast differentiation via the activation of ERK, JUNK, and miR-153/Runx2 signaling. Increases the secretion of Col I APL.	Inhibition of bone loss. Improved bone remodeling in pre-clinical models.	[69,70,71,72]
Kaempferol (Kaempferia galanga)	3,4′,5,7-Tetrahydroxyflavone		Attenuation of IL-1β-induced effects by inhibiting p38 MAPK/NF-κB pathways in chondrocytes.	Anti-inflammatory effect.	[74,75]
			Increases osteoblast differentiation via the activation of Wnt/β-catenin and mTOR signaling, increasing BMP-2, Rux-2, Osx, and Col I expression. Inhibits osteoclastogenesis by downregulating MAPK, c-Fos, and NFATc1.	Inhibition of bone loss and stimulation of bone formation.	[76,77,78,79,80,81]
Luteolin (Salvia tomentosa, Artemisia asiatica)	3,4′,5,7-Tetrahydroxyflavone		Attenuation of IL-1β-induced effects by inhibiting NF-κB pathways and the activation of Foxo3a in chondrocytes. Decreases the expression of COX-2, iNOS, MMPs, and ADAMTS-4,5. Attenuates cartilage degradation and increases Col II secretion.	Anti-inflammatory and anti-catabolic effects. Attenuation of cartilage degradation.	[83,84,85,86,87]
			Increases osteoblast differentiation via the regulation of ERK/Lrp-5/GSK-3β signaling, increasing BMP-7, Rux-2, Osx, Osc, APL, TGF-β1, and Col I expression. Inhibition of osteoclast differentiation.	Inhibition of bone loss and stimulation of bone formation.	[34,88,89,90,91,92,93,94]
Naringin (Citrus × paradisi)	Flavanone-7-O-glycoside		Alleviation of IL-1β/TNFα/LPS-induced effects via inhibiting MAPK p38 and NF-κB signaling and the activation of Foxo3a in chondrocytes. Decreases the expression of MMPs and ADAMTS-4,5. Attenuates cartilage degradation.	Anti-inflammatory and anti-catabolic effects. Attenuation of cartilage degradation.	[95,96,97,98]
			Increases osteoblast proliferation and differentiation. Increases the expression of Rux-2, Osx, Osc, BMP-2, OPN, and Col I expression. Inhibits osteoclast differentiation.	Inhibition of bone loss and promotes bone formation.	[99,100,101,102,103]
Puerarin (Pueraria lobate)	Isoflavone		Blocks the anti-catabolic effects in chondrocytes via the action of the AMPK/PGC-1α signaling pathway. Attenuates cartilage degradation.	Anti-inflammatory and anti-catabolic effects. Attenuation of cartilage degradation.	[105,106]
			Promotes bone formation via the activation of p38 MAPK, ERK1/2-Runx2, and Wnt/β-catenin signaling and by inhibiting TRPM3/miR-204 expression. Inhibits osteoclastogenesis by downregulating CREB/PGC1β/c-Fos/NFATc1 signaling.	Inhibition of bone loss and promotes bone formation.	[107,108,109,110,111,112,113,114]
Silibinin/Silymarin (Silybum marianum)	Flavone		Inhibition of IL-1β-induced effects by inhibiting PI3K/Akt and NF-κB signaling. Decreases the expression of iNOS, MMPs, and ADAMTS-4,5. Diminishes the secretion of NO, PEG2, TNF-α, and IL-6. Attenuates cartilage degradation and synovitis in vivo.	Anti-inflammatory, anti-oxidant, and anti-catabolic effects. Attenuation of cartilage degradation and synovitis.	[118,119,120]
			Induces osteoblast differentiation, increasing the expression of Runx-2, BMP-2, ALP, and Col I. Inhibits osteoclastogenesis by disturbing TRAF6-c-Src signaling.	Anti-oxidant and anti-apoptotic effects in osteoblasts. Inhibition of bone loss.	[121,122,123,124,125,126]
Wogonin (Scutellaria baicalensis)	O-methylated flavone		Inhibition of IL-1β-induced effects by inhibiting c-Fos/AP-1 and JAK/STAT signaling and activating ROS/ERK/Nrf2 signaling. Decreases the expression of iNOS, MMPs, and ADAMTS-4,5. Diminishes the secretion of NO, PEG2, TNF-α, and IL-6. Attenuates cartilage degradation and synovitis in vivo.	Anti-inflammatory, anti-oxidant, and anti-catabolic effects. Attenuation of cartilage degradation and synovitis.	[129,130,131,132,133,134]