Table 1 Effect of small molecules extracted from traditional Chinese medicine on osteoarthritis
From: Small molecules of herbal origin for osteoarthritis treatment: in vitro and in vivo evidence
Compound (TCM) | Model used | Study design | Delivery and dose | Effects/targets (downregulated↓, upregulated↑) | Pathway/mechanism | Reference | |||
|---|---|---|---|---|---|---|---|---|---|
Anti-inflammation | Anti-catabolism | Anabolism | Others | ||||||
Anemonin | h-chondrocytes | Pretreated for 1 h before 10 ng/mL IL-1β treatment for 24 h | 10 μM | IL-1β↓, IL-6↓, IL-8↓ | MMP-3↓, MMP-13↓ | Aggrecan↑ | Collagen X↓, p-IKKα/β↓, p-p65↓ | NF-κB | Wang et al. [58] |
h-articular cartilage | 10 ng/mL IL-1β with/without Anemonin for 4 days | 10 μM | MMP-13 positive cells↓, GAG release↓, proteoglycan loss↓ | Collagen II↑ | Collagen X positive cells↓ | ||||
Mouse | DMM-induced OA for 12 weeks | 2 mg/kg (i.a.) | MMP-13↓, ADAMTS-5↓, damage of articular cartilage structure↓ | Aggrecan↑, proteoglycan↑ | Chondrocyte hypertrophy↓, chondrocyte apoptosis↓; p-p65↓ | ||||
Resveratrol | Porcine chondrocytes | Pretreated for 24 h before 100 μg/mL AGEs treatment for 24 h | 25, 50, 75, 100 μM | iNOS↓, COX-2↓, NO↓, PGE2↓ | MMP-13↓ | Collagen II↑ | DNA-binding activity of NF-κB↓, IκBα level↑ in a dose-dependent manner; p-IKKα/β, p-ERK↓; NF-κB and AP-1 transcriptional activity↓; JNK activity↓ in a dose-dependent manner | NF-κB and AP-1 | Liu et al. [59] |
Porcine cartilage | Pretreated for 24 h before 100 μg/mL AGEs treatment for 72 h | 50, 100 μM | Proteoglycan release↓, cleavage products of aggrecan↓ | ||||||
Curcumin | Rat | MIA-induced OA for 2 weeks | 200 mg/kg (i.p.) | Inflammatory cells infiltration↓; IL-6↓, IL-1β↓, and TNF-α↓ in the synovial fluid | Orderly arranged chondrocytes with a smoother articular surface; Mankin score↓ | Joint diameter in OA rats↓; paw withdrawal threshold↑; TLR4↓, MyD88↓, p-IκBα↓, NF-κB↓ | TLR4/MyD88/NF-κB | Zhang et al. [60] | |
Amurensin H | Rat chondrocytes | Pretreated for 2 h before 10 ng/mL IL-1β treatment for 24 h | 2, 4, 8 μM | NO↓, iNOS↓, PGE2↓, COX-2↓, IL-6↓, IL-17↓, and TNF-α↓ in a dose-dependent manner | MMP-9↓ and MMP-13↓ in a dose-dependent manner | Collagen II↑, GAG↑ in a dose-dependent manner | Mitochondrial ROS↓ in a dose-dependent manner; TLR4↓, p-Syk↓ and TRAF6↓ in a time-dependent manner; p-p65↓ and nuclear translocation↓ | TLR4/Syk/NF-κB | Ma et al. [61] |
Mouse | ACLT-induced OA for 2 weeks | 10, 20 mg/kg (i.g) | cartilage loss↓, OA course↓ | ||||||
Paeonol | h-OA chondrocytes | Pretreated for 2 h before 10 ng/mL IL-1β treatment for 24 h | 12.5, 25, 50 μM | NO↓, iNOS↓, COX-2↓, and PGE2↓ in a dose-dependent manner | MMP-1↓, MMP-3↓, MMP-13↓ in a dose-dependent manner | p-p65↓, p-IκB↓ and p-PI3K↓, p-AKT↓ | PI3K/AKT/NF-κB | Lou et al. [62] | |
Mouse | DMM-induced OA for 8 weeks | 30 mg/kg (i.p.) | OARSI score↓ | ||||||
Nobiletin | h-OA chondrocytes | Pretreated for 2 h before 10 ng/mL IL-1β treatment for 1 h | 10, 20, 40, 80 μM | iNOS↓, COX-2↓, PGE2↓, NO↓, IL-6↓, and TNF-α↓ in a dose-dependent manner | MMP-13↓ and ADAMTS-5↓ in a dose-dependent manner | Aggrecan↑ and collagen II↑ in a dose-dependent manner | p-p65↓, p-IκB↓, p-PI3K↓, p-AKT↓, and NF-κB promoter luciferase activity↓ in a dose-dependent manner | PI3K/AKT/NF-κB | Xie et al. [63] |
Mouse | DMM-induced OA for 8 weeks | 20 mg/kg (i.g) | Protected the structure of articular cartilage and maintained the proteoglycan; OARSI score↓ | Subchondral bone thickness↓ | |||||
Trans-cinnamaldehyde | SW1353 cell line h-OA chondrocytes | Pretreated for 2 h before 10 ng/mL IL-1β treatment for 6 h | 2, 5, 10 μg/mL | MMP-1↓, MMP-3↓, MMP-13↓, ADAMTS-4↓, and ADAMTS-5↓ in a dose-dependent manner | p-IκB𝛼↓, p-p38↓, p-JNK1/2↓ in a dose-dependent manner | NF-κB and p38-JNK | Xia et al. [64] | ||
Rat | MIA-induced OA for 4 weeks | 50 mg/kg (i.p.) | More abundant matrix and smoother superficial zone of the cartilage; OARSI score↓ | ||||||
Ligustrazine | h-OA chondrocytes | Co-treated with 5 ng/mL IL-1β for 24 h | 0.5, 1, 2 μM | IL-1↓, IL-6↓, TNF-α↓ | MMP-13↓ | Collagen II↑, aggrecan↑, GAG↑ | SOD1↑, SOD2↑, SOX9↑, ROS production↓, and MDA↓; nuclear p65↓, p-IκBα↓, and cytoplasmic p65↑; cell apoptosis↓ | SOX9/NF-κB | Yu et al. [65] |
Knee OA patients | 5 weeks | 25, 50, 100 μg/L (po) | IL-1↓, IL-6↓, and TNF-α↓of the joint effusions in a dose-dependent manner | SOD↑ and MDA↓ level of the joint effusions in a dose-dependent manner | |||||
Piperine | h-OA chondrocytes | Pretreated for 2 h before 5 ng/mL IL-1β treatment for 24 h | 10, 50, 100 μg/mL | NO↓, PGE2↓, iNOS↓, and COX-2↓ in a dose-dependent manner | MMP-3↓ and MMP-13↓ in a dose-dependent manner | Nuclear p65↓, p-IκBα↓, p-NF-κB↓ | NF-κB | Ying et al. [66] | |
Crocin | Rabbit chondrocytes | Pretreated for 1 h before 5 ng/mL IL-1β treatment for 24 h | 5, 25, 50, 100 μM | MMP-1↓, MMP-3↓, MMP-13↓ | IκBα↑, NF-κB-dependent transcriptional activity↓ | NF-κB | Ding et al. [67] | ||
Rabbit | ACLT-induced OA | 5, 100 μM (i.a) | MMP-1↓, MMP-3↓, MMP-13↓; cartilage degradation↓ | Mankin score↓ | |||||
Leonurine | Mouse chondrocytes | Pretreated for 2 h before 10 ng/mL IL-1β treatment for 24 h | 5, 10, 20 μM | NO↓, PGE2↓, IL-6↓, TNF-α↓, COX-2, and iNOS↓ in a dose-dependent manner | MMP-3↓, MMP-13↓, ADAMTS-5↓ | Aggrecan↑, collagen II↑ | p-p65↓, p-IκB↓ in a dose-dependent manner | NF-κB | Yin et al. [68] |
Mouse | DMM-induced OA for 6 weeks | 30 mg/kg (i.p) | OARSI score↓ | Subchondral bone thickness↓, synovitis↓, fibrous cartilage↓ | |||||
Isofraxidin | h-OA chondrocytes | Pretreated for 2 h before 10 ng/mL IL-1β treatment for 24 h | 1, 10, 50 μM | NO↓, PGE2↓, COX-2, and iNOS↓ in a dose-dependent manner | MMP-1↓, MMP-3↓, MMP-13↓, ADAMTS-4↓, ADAMTS-5↓ | Aggrecan↑, collagen II↑ | p-p65↓, p-IκB↓ | NF-κB | Lin et al. [69] |
Juglanin | h-OA chondrocytes | Pretreated for 2 h before 10 ng/mL IL-1β treatment for 24 h | 10, 20, 40 μM | NO↓, PGE2↓, COX-2, iNOS↓, TNF-α↓, and IL-6↓ in a dose-dependent manner | MMP-1↓, MMP-3↓, MMP-13↓, ADAMTS-4↓, ADAMTS-5↓ | p-p65↓, p-IκB↓ | NF-κB | Chen et al. [70] | |
Scutellarin | Mouse chondrocytes | Pretreated for 24 h before 10 ng/mL IL-1β treatment for 24 h | 15, 30, 60 mM | COX-2↓, iNOS↓, PGE2↓, IL-6↓, TNF-α↓ | MMP13↓, ADAMTS-5↓ | Aggrecan↑, collagen II↑ in a dose-dependent manner | Cytoplasmic IκBa↑, nuclear p65↓ in a dose-dependent manner; nuclear Nrf2↑, cytoplasmic HO-1↑ | NF-κB and Nrf2/HO-1 | Luo et al. [71] |
Mouse | DMM-induced OA for 8 weeks | 50 mg/kg (i.p) | COX-1↑, COX-2↓, mPGES-1↑, mPEFS-2↓ | Smoother cartilage surface; loss of proteoglycan↓; OARSI score↓ | |||||
Oxymatrine | h-OA chondrocytes | Treated with 1 μg/mL LPS | 0.5, 1, 2 mg/mL | IL-6↓, IL-8↓, TNF-α↓ | MMP-2↓, MMP-9↓, MMP-13↓ | p-p65↓, p-ERK↓, p- JNK↓, p-p38↓ | NF-κB and MAPKs | Jiang et al. [72] | |
h-OA articular cartilage | Co-treated with 10 μg/mL LPS for 7 or 14 days | GAG release↓; proteoglycan loss↓ | Collagen II↑ | ||||||
Mouse | ACLT-induced OA for 2 weeks | 25, 50 mg/kg (i.p.) | MMP-9 and MMP13-positive chondrocytes↓; destruction of cartilage↓ | Cell apoptosis↓, p-65-positive chondrocytes↓ | |||||
Hinokitiol | Rat chondrocytes | Pretreated for 2 h before 5 ng/mL IL-1β treatment for 24 h | 10, 20, 40, 80 μM | MMP-1↓, MMP-3↓, and MMP-13↓ in a dose-dependent manner | Collagen II↑ | Wnt/β-catenin | Li et al. [73] | ||
Rat | MIA-induced OA for 1 week | 20 μL, 80 μM (i.a.) | MMP-1↓, MMP-3↓, and MMP-13↓ in a dose-dependent manner | Mankin score↓ | |||||
Tetrandrine | Rabbit chondrocytes | Pretreated for 1 h before 5 ng/mL IL-1β treatment for 24 h | 5, 10, 20 μM | MMP-1↓, MMP-3↓, and MMP-13↓ | TIMP-1↑ | β-Catenin↓ | Wnt/β-catenin | Zhou et al. [74] | |
Rabbit | ACLT-induced OA for 1 month | 6 μg (i.a) | MMP-1↓, MMP-3↓, MMP-13↓; bone wear↓, cartilage degradation↓ | TIMP-1↑; Mankin score↓ | β-Catenin↓ | ||||
Polygalacic acid | Rat chondrocytes | Co-treated with 10 ng/mL IL-1β for 24 h | 50, 100 μM | COX-2↓ in a dose-dependent manner | MMP-3↓, MMP-9↓, MMP-13↓ in a dose-dependent manner | β-Catenin↓, p-p38↓, p-ERK↓, p-JNK↓ | Wnt/β-catenin and MAPKs | Xu et al. [75] | |
Rat | DMM-induced OA for 6 weeks | 100 μM (i.a.) | COX-2↓ | Mankin score↓ | |||||
Icariin | SW1353 cell line | Pretreated for 1 h before 10 ng/mL IL-1β treatment for 24 h | 5, 10, 20, 40, 80, 100 μM | MMP-13↓ at 10 𝜇M and 20 μM | p-p38↓, p-p46↓, p-p54↓, β-catenin↓ | Wnt/β-catenin and MAPK | Zeng et al. [76] | ||
Rat | ACLT-induced OA for 6 weeks | 20 μM (i.a) | MMP-13↓ | Mankin score↓ | p-p38↓, P-p46↓, P-p54↓, β-catenin↓ | ||||
Zingerone | SW1353 cell line | Treated with 2 ng/mL IL-1β | 10, 20, 40 μM | TNF-α↓, IL-6↓, and IL-8↓in a dose-dependent manner | MMP-13↓ in a dose-dependent manner | p-p38↓, p-JNK↓ | p38 and JNK/MAPKs | Ruangsuriya et al. [77] | |
Porcine cartilage | Treated with 10 ng/mL IL-1β for 5 days or 30 days | 10, 20, 40 μM | MMP-13↓, s-GAG release↓, hyaluronic acid release↓ | Uronic acid↑, collagen↑ | |||||
Geniposide | Rabbit OA chondrocytes | 24 h | 80 μg/mL | IL-1β↓, TNF-α↓ | MMP-13↓ | Collagen II↑ | p-p38↓ | p38/MAPK | Chen et al. [78] |
Rabbit | ACLT-induced OA for 2 weeks | 40 mg/kg (i.g.) | IL-1β↓, TNF-α↓, NO↓ | MMP-13↓ | |||||
Ginsenoside Rb1 | SW 1353 cell line | Pretreated for 1 h before 10 ng/mL IL-1β treatment for 24 h | 80 μM | MMP-13↓ | Collagen II↑ | Notch1↓, JAG1↓ | Notch | Wang et al. [79] | |
Rat | ACLT-induced OA for 6 weeks | 0.3 mL, 80 mM (i.a.) | MMP-13↓; cartilage lesions↓ | Collagen II↑; Mankin score↓ | Notch1↓, JAG1↓ | ||||
Halofuginone | Mouse and rat | ACLT-induced OA | 1 mg/kg (i.p.) | MMP-13↓, ADAMTS-5↓, proteoglycan loss↓ | Collagen II↑, aggrecan↑, lubricin↑; Mankin score↓ | Collagen X↓; calcification of articular cartilage↓; aberrant angiogenesis↓ in subchondral bone; subchondral bone remodeling↑; Th17-induced osteoclastic bone resorption↓; p-Smad2↓, pSmad2/3-positive cells↓ | TGF-β/Smads | Cui et al. [80] | |
Celastrol | Rat chondrocytes | Pretreated for 12 h before 10 ng/mL IL-1β treatment for 18 h | MMP-13↓, ADAMTS-5↓ | SDF-1/CXCR4 | Wang et al. [81] | ||||
Rat | MIA-induced OA for 2 weeks | 1, 2 mg/kg (i.a.) | MMP-3↓, MMP-9↓, MMP-13↓, Runx2↓ | Collagen II↑, aggrecan↑, proteoglycan↑; OARSI score↓ | SDF-1↓ and CXCR4↓ in a dose-dependent manner | ||||
Wogonin | h-OA chondrocytes | Pretreated for 2 h before 1 ng/mL IL-1β treatment for 24 h | 10, 25, 50 μM | IL-6↓, COX-2↓, PGE2↓, iNOS↓, NO↓ | MMP-13↓, MMP-3↓, MMP-9↓, and ADAMTS-4↓ in a dose-dependent manner | Collagen II↑, aggrecan↑ | ROS↓ in a dose-dependent manner; Nrf2↑, HO-1↑, SOD-2↑, NQO-1↑, and GCLC↑; p-ERK1/2↑ | ROS/ERK/Nrf2 | Khan, et al. [82] |
h-OA cartilage | Pretreated for 2 h before 25 ng/mL IL-1β treatment for 72 h | 10, 25, 50 μM | s-GAG release↓; proteoglycan loss↓ | Collagen II↑ in a dose-dependent manner | |||||