Table 2 Studies of Epimedium and its active ingredients in maintaining the structures and functions of cartilage to treat OA
From: Effects of genus Epimedium in the treatment of osteoarthritis and relevant signaling pathways
References | Assay type | Component of Epimedium | Concentration/dosage | Cells/model | Effects | Mechanisms |
|---|---|---|---|---|---|---|
Anti-inflammation and anti-OS | ||||||
Ziadlou [53] | In vitro | Epimedin C | 25 µM | Human knee OA chondrocytes treated by IL-1β/TNF-α | Matrix degradation: MMP1↓, MMP3↓, MMP13↓ Inflammatory factors: COX-2↓ Matrix formation: Col2↑, aggrecan↑, GAG/DNA↑ | Promoting the extracellular matrix formation through anti-inflammatory |
Wang [57] | In vitro | Icariin | 1 µM | Mouse chondrocytes (ADTC5) treated by TNF-α | Chondrocyte viability↑ Signal pathway: p-IKKα/β/IKKα/β↓, p-IκB/IκB↓, p-NF-κB/NF-κB↓, HIF-2α↓ | Relieving articular cartilage damage by inhibiting NF-κB/HIF-2α signaling pathway to reduce inflammation |
In vivo | 3D alginate-gelfoam complexes incorporated with Icariin | 1 µM | Knee cartilage defect mouse model | Histopathology: relatively intact cartilage surface, substantial subchondral bone, ICRS II score↑ Matrix formation: Sox9↑, aggrecan↑, Col2α↑ Matrix degradation: MMP9↓, ADAMTS-5↓ Signal pathway: HIF-2α positive cells↓, NF-κB positive cells↓ | ||
Sun [58] | In vitro | Hyperoside | 10, 20 and 40 μM | Il-1β stimulated C57BL/6 mouse chondrocytes | Inflammatory factors: iNOS↓, COX2↓ Matrix degradation: ADAMTS5↓, MMP3↓, MMP13↓ Matrix formation: Sox9↑, Col2↑, aggrecan↑ OS factor: ROS↓ Apoptosis-related proteins: Bcl-xl↑, Bax↓, Cytochrome C↓, cleaved-caspase-9↓, cleaved-caspase-3↓ Signal pathway: p-PI3K/PI3K↓, p-AKT/AKT↓, p-ERK/ERK↓, p-JNK/JNK↓, p-C-JUN↓, p-p65/p65↓, p-IκBα↓, IκBα↑, Nrf2↑, HO-1↑ | Alleviating OA inflammation and matrix loss by inhibiting PI3K/AKT/NF-κB and MAPK signaling pathways, while enhancing Nrf2/HO-1 signaling pathway; anti-apoptosis of chondrocytes through Nrf2/ROS/Bax/Bcl-xl axis |
In vivo | Hyperoside | 20 mg/kg | OA model established by the destabilized medial meniscus surgery in C57BL/6 mice | Histopathology: smoother and more intact cartilage surface, OARSI score↓ Signal pathway: Nrf2 positive cells↑ | ||
Zuo [59] | In vitro | Icariin | 10–3 µM | IL-1β stimulated human chondrocytes (icariin pretreatment) | Matrix formation: GAG↑ Matrix degradation: MMP3↓, MMP9↓, MMP13↓, ADAMTS-4↓ Anti-OS factors: Nrf2↑, SOD-1↑, SOD-2↑, GPX↑, NQO-1↑, HO-1↑, Keap1↓ OS factor: ROS↓ | Inhibiting OA matrix degradation by Nrf2/ARE signaling pathway |
Zeng [60] | In vitro | Icariin | 20 μM | IL-1β-stimulated human SW1353 chondrosarcoma cells | Matrix degradation: MMP1↓, MMP3↓, MMP13↓ Signal pathway: p-p38↓, p-pERK↓, p-pJNK↓ | Playing a role in cartilage protection by inhibiting the MAPK signaling pathway |
Li [61] | In vivo | Icariin | 20 mg/kg | Knee OA rat model established by the modified Hulth method | Histopathology: increase of cartilage thickness and bone trabeculae, smoother cartilage surface Micro-CT: BV/TV↑, BMD↑ Bone resorption markers: TRACP-5b↓, CTX-1↓ Bone formation markers: 1,25(OH)2D3↑, OCN↑ Bone remodeling related indicator: TGF-β↓, BMP-4↓, Smad4↓, p-Smad1/5/9/Smad1/5/9↓ Pain-related indices: TWL↑, MWT↑ Inflammatory factors: IL-1β↓, TNF-α↓ Matrix degradation: MMP3↓, MMP13↓ | Treating OA and OA pain by the inhibition of TLR4/MyD88/NF-κB signaling pathway and neuromodulation |
In vitro | Icariin | 20 μM | LPS-induced knee joint chondrocytes of SD rats | Matrix formation: Col2↑ Matrix degradation: MMP3↓ Signal pathway: TLR4↓, MyD88↓, TRAF-6↓, NF-κB p65↓, IKK-α↓, IKK-β↓ | ||
In vivo | Icariin | 20 mg/kg | Knee OA rat model established by the modified Hulth method | Neuropeptides: NPY↓, NPY1R↓, SP↓, 5-HT1B R↓, VIP↑ Resting-state fMRI: decrease of ReHo in the cortex, hypothalamus and midbrain, increase of the hippocampus ReHo Pain-related genes: Inα↑, Rtn4↓ | ||
Inhibiting chondrocyte apoptosis, pyroptosis, and improving autophagy | ||||||
Mi [62] | In vitro | Icariin | 10 μM | TNF-α treated chondrocytes in SD rats | Inflammatory factors: IL-1↓, IL-6↓, IL-12↓ Autophagy markers: Atg 5↑, Atg 7↑, LC3-II↑ Delay cell cycle arrest Apoptosis-related proteins: Bcl-2↑, Bax↓, caspase-3↓, caspase-9↓ OS factors: NO↓, ROS↓ Matrix degradation: MMP 3↓, MMP 9↓ Signal pathway: p-p65/p65↓, IκBα↑ | Anti-apoptosis and enhancing autophagy in chondrocytes by the inhibition of NF-κB signaling pathway |
Wang [63] | In vitro | Icariin | 30 μM | IL-1β stimulated human chondrocyte cell line CHON-001 and mouse chondrocyte cell line ATDC5 | lncRNA: CYTOR↑ Cell apoptosis: apoptosis rate of chondrocytes↓ Inflammatory factors: IL-6↓, IL-8↓, TNF-α↓ | Inhibiting chondrocyte apoptosis by the up-regulation of CYTOR |
Zhou [64] | In vitro | Epimedium ethanol extraction | 80 mg/L | SD rat chondrocytes of the knee joint | Histopathology: improvement of chondrocyte morphology Cell apoptosis: early apoptosis rate↓, late apoptosis and necrosis rate↓, total apoptosis rate↓ | The inhibition of chondrocyte apoptosis |
Zu [56] | In vitro | Icariin | 5, 10 and 20 μM | LPS-treated Wistar rat chondrocytes of knee joint | Inflammatory factors: IL-1β↓, IL-18↓ Matrix degradation: MMP1↓, MMP13↓ Matrix formation: Col2↑ Pyroptosis-related proteins: NLRP3↓, ASC↓, caspase-1↓, GSDMD↓ | Inhibiting chondrocyte pyroptosis mediated by NLRP3 |
In vivo | Icariin | 20 μM, 0.3 mL | Intra-articular injection of monosodium iodoacetate in Wistar rats | Histopathology: reduction of cartilage erosion Pyroptosis-related proteins: NLRP3 positive cells↓, NLRP3↓ Inflammatory factors: IL-1β↓, IL-18↓ Matrix degradation: MMP1↓, MMP13↓ Matrix formation: Col2↑ | ||
Tang [65] | In vitro | Icariin | 40, 60 and 80 μM | SD rat chondrocytes of the knee joint | Cell apoptosis: apoptosis rate of chondrocyte↓ Autophagy markers: ATG7↑, LC3-II/LC3-I↑ Signal pathway: PI3K↓, p-AKT1/AKT1↓, p-mTor/mTor↓, p-p70S6K/p70S6K↓ | Enhancing autophagy and alleviating chondrocytes apoptosis through the inhibition of PI3K/AKT/mTOR signaling pathway |
In vivo | Icariin | 20, 40 and 80 mg/kg | Knee OA rat model established by the modified Hulth method | Histopathology: OARSI score↓ Autophagy markers: Beclin-1↑, ATG7↑, LC3-II/LC3-I↑ Signal pathway: PI3K↓, p-AKT1/AKT1↓, p-mTor/mTor↓, p-p70S6K/p70S6K↓ | ||
Chen [66] | In vitro | Icariin | 40 μM | IL-1β-mediated human SW1353 cells (icariin pretreatment) | Matrix degradation: MMP3↓ Matrix formation: Col2↑ Autophagy markers: LC3-II/LC3-I↑, Beclin-1↑, p62↓, ULK1↑ Signal pathway: p-PI3K/PI3K↓, p-AKT/AKT↓, p-mTor/mTor↓ | Alleviating OA by PI3K/Akt/mTOR/ULK1 signaling pathway |
Liu [67] | In vitro | Icariin | 0.1, 1 and 10 μM | Oxidation, glucose and serum deprivation-induced rabbit BMSCs (Icariin pretreatment) | ER stress-related proteins: BIP↓, ATF4↓, CHOP↓, p-IRE1a↓, XBP-1s↓ Apoptosis-related proteins: caspase-3↓, cleaved caspase-3↓, PARP↓, cleaved-PARP↓ Autophagy marker: LC3-I↑, p62↑, Beclin-1↓, ATG5↓, LC3 II↓ Signal pathway: p-ERK↓, p-P38↓, p-JNK↓ | Inhibiting ER stress in BMSCs, thereby reducing apoptosis and autophagy through the inhibition of the MAPK signaling pathway |
Wang [68] | In vitro | Icariin | 1 µM | Alginate-C57BL/6 mouse chondrocytes 3D complex (Anoxic model) | Matrix formation: proteoglycan↑, Sox9↑ Chondrocyte viability↑ Signal pathway: HIF-1α↑ Glucose transport and anaerobic glycolytic enzymes: GLUT1↑, PGK1↑, PDK1↑, G6PD↑ | Promoting HIF-1α expression and anaerobic glycolysis to increase chondrocyte viability |
Promoting chondrogenic differentiation of mesenchymal stem cells | ||||||
Zhu [69] | In vitro | Icariin-loaded hydrogel | 29.6, 147.8 and 738.9 μM | BMSCs | Cell proliferation and viability↑ Chondrogenic markers: Sox 9↑, Col2α1↑, aggrecan↑, HIF-1α↑ Signal pathway: Dvl1↑, β-catenin↑, GSK-3β↓ | Promoting BMSCs chondrogenic differentiation through Wnt/β-catenin signaling pathway |
In vivo | Icariin-loaded hydrogel + BMSCs | 147.8 μM, 0.4 mL | OA rat model established by destabilizing medial meniscus surgery | Histopathology: generally intact articular cartilage, OARSI score↓, Mankin score↓ Chondrogenic markers: Sox 9↑, Col2α1↑, aggrecan↑, HIF-1α↑ Signal pathway: Dvl1↑, β-catenin↑, GSK-3β↓ Inflammatory factors: IL-10↑, MMP-13↓ Pain-related indices: WBI↑, PWT↑ | ||
Tang [70] | In vitro | Icariin | 0.1, 1 and 10 μM | Oxygen‐glucose deprivation/reoxygenation‐induced rabbit BMSCs (icariin pretreatment) | BMSCs proliferation↑ Matrix formation: GAG↑ Chondrogenic markers: BMP2↑, aggrecan↑, Col2α1↑, actin cytoskeleton↑ | Accelerating cartilage defect repair by promoting BMSC chondrogenic differentiation under the oxygen–glucose deprivation conditions |
In vivo | Icariin + BMSCs | 10 μM | A cartilage defect on the rabbit trochlear surface of the femur | Histopathology: ICRS score↑, production of smooth surface and integrated cartilage structure, increase of chondrocytes and extracellular matrix Matrix formation: Col2α1↑ | ||
Wang [71] | In vitro | Icaritin + GDF-5 | 5 μM | BMSCs in SD rats | Chondrogenic markers: aggrecan↑, Col2↑, Sox9↑ Signal pathway: DVL1↑, β-catenin↑, Gsk3β↓ | Promoting BMSC chondrogenic differentiation through Wnt/β-catenin signaling pathway |
Wang [72] | In vitro | Icariin + TGF-β3 | 1 µM | Rat BMSCs | Chondrogenic markers: Sox9↑, Col2↑, aggrecan↑ Fibrocartilage markers: Col1α1 (no increase) Hypertrophy markers: ALP (no increase) | Promoting chondrogenic differentiation with no effects on hypertrophy |
Wang [73] | In vitro | Icariin + TGF-β3 | 1 µM | Rat BMSCs/self-assembling peptide nanofiber hydrogel scaffold | Chondrogenic markers: Sox9↑, Col2α1↑, Col2↑ Increase of chondrocyte-like rounded morphology Hypertrophy markers: ColX (no increase), ALP (no increase), Col1α1↓ | Promoting BMSC stable chondrogenic differentiation in self-assembled peptide nanofiber hydrogel scaffolds |
Luo [74] | In vivo | Icariin | 25 mg/kg | OA model established by the transection of anterior cruciate ligament in C57/6J mice | Histopathology: subchondral bone formation↓, cartilage thickness↑, OASRI score↓ Matrix formation: GAG↑, Sox9↑, Col2α1↑ Hypertrophy markers: ColX↓, MMP13↓ | Promoting chondrocyte differentiation and inhibiting chondrocyte hypertrophy by the down-regulation of IHH-related genes and the upregulation of PTHrP |
In vitro | Icariin | 1 µM | Chondrocytes in C57/6J mouse OA model | Matrix formation: proteoglycan↑, Sox9↑, aggrecan↑ Bone formation markers: Runx2↓ Hypertrophy markers: MMP13↓, ColX↓ Signal pathway: PTHrP↑, IHh and its regulated genes (IHh↓, CyclinD1↓, Gli1↓, Ptch1↓) | ||
Bahrami [75] | In vitro | Icariin + TGF-β3 | 10 µM | Human AMSCs- fibrin constructions | Chondrogenic markers: Sox9↑, Col2↑, aggrecan↑ Fibrocartilage markers: Col1↓ Hypertrophy markers: ColX↓ | Promoting AMSC chondrogenic differentiation and reducing hypertrophy effects |
Yu [76] | In vivo | Icariin + AMSCs | 6 × 104 mg/L | Rabbit OA model established by the modified Hulth method | Histopathology: smooth and intact cartilage surface, Mankin score↓ Cell apoptosis: apoptosis rate of chondrocytes↓ Inflammatory factors: NO↓, IL-1↓, TNF-α↓ Signal pathway: TLR4↓, MyD88↓, TRAF6↓, p65↓ | AMSCs with icariin pre-intervention can treat OA by inhibiting TLR4/NF-κB signaling pathway |