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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