Research progress in mechanism of traditional Chinese medicine in the treatment of Knee Osteoarthritis

QIN Shu-ying, SU Jing, WEI Cheng-yu, CHEN Zhi-fen, LIU Yong-li, LI Liu-zhen, LEI Long-ming

1.Graduate School of Guangxi University of Traditional Chinese Medicine, Nanning 530200, China

2.The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning 530023, China

Keywords:

ABSTRACT Knee osteoarthritis (KOA) is a chronic degenerative Osteoarthritis disease.The majority of patients with knee osteoarthritis were elderly patients.The disease not only greatly affects the work and life of patients but also brings serious burden to families and society.The traditional Chinese medicine has a long history in China, which has shown a multi-pathway and multitarget mechanism for the prevention and treatment of knee osteoarthritis.According to the properties of Chinese medicine, it was divided into four categories:drugs to promote blood circulation and remove blood stasis, drugs to clear heat, drugs to dispel wind dampness and drugs to tonify deficiency.In addition, the relevant literatures at home and abroad in recent five years were reviewed to summarize and generalize the mechanism of traditionalChinese medicine in the treatment of knee osteoarthritis, in order to provide reference for the treatment of knee osteoarthritis with traditional Chinese medicine.✉Corresponding author: LEI Long-ming, Chief Physician, Professor, M.D.E-mail: leilongming@126.com.

1.Introduction

Knee Osteoarthritis (KOA) is a type of chronic arthritis characterized by Knee cartilage degeneration and subchondral bone hyperosteogeny.Its clinical symptoms are joint pain, swelling, and dysfunction.[1]KOA has a high incidence and complex pathogenesis,which is currently believed to be closely related to age, obesity, joint trauma, living environment and other factors.If the disease is not treated in time, severe cases will lead to disability.Therefore, how to prevent and treat KOA has become an important global public health issue[2].For patients with early and middle stage KOA, nonsurgical therapy is the preferred treatment, mainly including physicaltherapy and pharmacotherapy.Studies have shown that non-steroidal antiinflammatory drugs and glucocorticoids are mainly used in the treatment of KOA, but both have certain limitations[3].For example,although NSaids are effective analgesics and anti-inflammatory drugs, long-term use increases the risk of gastrointestinal discomfort, acute kidney injury, cardiovascular damage and other complications, while intraarticulatory injection of glucocorticoids usually provides only a short period of relief[4].Therefore, it is an important research direction to find safe, effective, low-cost and less side effect KOA treatment drugs.

In recent years, some progress has been made in the treatment of KOA with Traditional Chinese medicine.Clinical studies have shown that the mild use of traditional Chinese medicine in the prevention and treatment of KOA can alleviate the patients’ adverse reactions,and improve the symptoms of knee joint movement limitation or pain, and thus improve their quality of life.Many basic experiments started from the molecular mechanism, and confirmed that Chinese medicine can inhibit the inflammatory response,resist oxidative stress response, regulate the balance of cartilage metabolism, improve local microcirculation, and play an analgesic role in KOA.Based on this, this paper reviewed the literatures related to the treatment of KOA by Traditional Chinese medicine at home and abroad in the past five years, and divided the single traditional Chinese medicine into promoting blood circulation and removing blood stasis, clearing heat, dispeling wind and dampness,reinforcing deficiency and other kinds of traditional Chinese medicine according to the property of traditional Chinese medicine,and summarized the mechanism of action of traditional Chinese medicine in the treatment of KOA, in order to find new ideas and directions.

2.Understanding of Chinese medicine on knee osteoarthritis

Knee osteoarthritis belongs to the categories of “Bizheng” and“Gubi” in Chinese medicine..The mainstream of traditional Chinese medicine doctors believes that the disease is the deficiency of the standard, “ancient and modern medical mirror” that “bi because of yuan jing internal deficiency, kidney Yang deficiency, feel the external evil, can not dispel the powder, bo in the meridians, left in the joint or internal injection caused by bone”.Deficiency of liver and kidney and deficiency of healthy qi are the fundamental causes of KOA.” Plain ask Bi Theory” says: “wind, cold and wet three miscellaneous qi, combined to become bi.”The results showed that wind, cold and dampness were the inducing factors of KOA.The traditional Chinese medicine puts forward that “the vital qi exists in the body, and the evil cannot be dried”.Therefore, it is believed that the etiology and pathogenesis of KOA lies in the deficiency of liver and kidney, the loss of muscles and bones, and the stagnation of qi and blood caused by the invasion of wind, cold and dampness,and the obstruction of meridian and collateral.Based on this, the TCM syndrome types of KOA can be summarized as: qi stagnation and blood stasis type, wind-cold obstruction type, damp-heat accumulation type and liver and kidney deficiency type[5].Therefore,the treatment method of this disease advocates treating both the symptoms and root causes, such as activating blood circulation and removing blood stasis, dispersing cold and dredging collateral,eliminating wind and dehumidifying, clearing heat and benefiting dampness, and supplementing liver and kidney etc.

3.Chinese medicine for knee osteoarthritis

3.1 Drugs for promoting blood circulation and removing blood stasis

3.1.1 Turmeric

Turmeric has the effect of breaking blood, promoting qi, clearing collaterals and relieving pain.Curcumin is a polyphenolic substance extracted from the rhizome of turmeric.Its pharmacological effects can be divided into anti-inflammatory, anti-mutagenic and anti-cancer activities[6].Yan[7] et al.found that the inflammatory and catabolic responses of KOA chondrocytes are related to the activation of Toll-like receptor 4 (TLR4), and curcumin can downregulate the expression of TLR4 and its downstream nuclear factor-κB (NF-κB) P65 protein and gene in synovium tissue, and inhibit synovium inflammation.In the rat KOA model, curcumin can increase the pain threshold of rats, increase the thickness of articular cartilage, and promote the repair of damaged articular cartilage[8].At the same time, curcumin can induce the enhancement of autophagy in chondrocytes by activating the extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway and inhibiting the protein kinase B(Akt)/ mammalian target of Rapamycin (mTOR)signaling pathway strengthen to maintain cartilage homeostatic and protect chondrocytes from sublethal injury[9].In addition, curcumin can also play an anti-KOA effect in a number of ways: Reducing chondrocyte apoptosis and promoting chondrocyte proliferation by mediating Wnt/β-catenin signaling pathway[10-11]; reducing the expression of matrix metalloproteinases(MMPs)by inhibiting NFκB signaling[12], Increases the ability of chondrocyte mitochondria to combat oxidative stress by activating the Janus kinase 2(JAK2)/Signal transduction and transcriptional activator 3(STAT3) signaling pathway[13].

3.1.2 Ligusticum wallichii

Ligusticum wallichii is one of the traditional Chinese medicines commonly used by the department of orthopedics and traumatology.Tetramethylpyrazine is an alkaloid active substance extracted from Ligusticum ligusticum, which can dilate blood vessels and improve tissue microcirculation, and can be used in the treatment of KOA[14].Studies have found that tetramethylpyrazine can reduce the inflammatory response in RATS of KOA.It is speculated that the mechanism might be related to the down-regulation of the expression level of vascular endothelial factor (VEGF) to inhibit angiogenesis[15].Some scholars have further verified the above conjecture through experiments:After gavage with ligustrezine,the expression level of miR-20b, an anti-angiogenic gene targeting VEGF, was up-regulated in the cartilage of KOA rats, and the expression of VEGF mRNA was inhibited, thereby inhibiting intraarticular chondral angiogenesis[16].Ligustrezine can promote the expression of bone morpectin 2(BMP-2) and Smad1 protein in the cartilage of KOA rats induced by papain, thereby promoting the expression of proteoglycan and type II collagen, and accelerating the process of cartilage repair[17].

3.1.3 Achyranthes bidentata

Achyrantha bidentata has the effect of supplementing liver and kidney, strengthening muscles and bones, removing blood stasis and passing meridian, and can be anti-inflammatory, antioxidant and anti-apoptosis, playing an important role in the treatment of KOA[18].Studies have shown that total saponins of achyrantha bidentata have a good therapeutic effect on KOA rabbits, which is shown to relieve the range of motion of the rabbit knee and reduce synovial inflammation.It is inferred that the therapeutic mechanism is related to the reduction of inflammatory factors, chemokines, matrix metalloproteinases and other cytokines in the synovial fluid of the knee joint[19-20].The total saponins of Achybidentata bidentata were inculcated into KOA rabbit model.6 weeks later, the cell viability and cell number of the experimental group were increased compared with the blank group and control group under electron microscope.TaqMan real-time fluorescence quantitative PCR results showed that: The mRNA expression of type ⅱ collagen increased, and the mRNA expression of hypoxia-inducing factor-1α(HIF-1α) and VEGF decreased, suggesting that the total saponins of ACHYranthae radix could improve the hypoxia-tolerance and reduce inflammatory factors of chondrocytes by inhibiting hiF-1 signaling pathway[21].By upregulating the expression of superoxide dismutase (SOD) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and downregulating the expression of MMP-13, the oxidative stress response and extracellular matrix degradation can be reduced, thus improving KOA degeneration[22].

3.1.4 Rhizoma drynariae

It is pointed out in “Materia Medica Gpicking” that the bone is broken and the bone is broken, which has the functions of promoting blood circulation and relieving pain, tonifying kidney and strengthening bone.Studies have shown that the formation of abnormal blood vessels is closely related to KOA, and the severity of KOA is aggravated with the increase of VEGF levels in plasma and synovial fluid[23].The total flavonoids of Bsa can reduce the expression levels of HIF-1αand VEGF proteins in synovial tissue and prevent the formation of new blood vessels, thus improving local microcirculation[24].In KOA, a balance between MMPs and TIMPs is essential for cartilage protection.No cytotoxic effect was found in SW1353 cells induced by IL-1β for 1h, but all the flavonoids could inhibit the activation of NF-κB and phosphatidilinoinosiol 3 kinase(PI3K)/AKT pathway.The expression of MMPs (including MMP-1,MMP-3 and MMP-13) was down-regulated, and the expression of TIMP-4 was up-regulated to regulate cartilage matrix metabolism[25].In vivo and in vitro experiments showed that:Naringin can reduce phosphorylation of the upstream target of NF-κB pathway IκB ,and reduce pain behavior of KOA rats by inhibiting NF-κB pathway.The effect of naringin in 40 mg/kg dose group was more significant than that in 20 mg/kg dose group.At the same time, the expression of catabolism marker MMP-13 and depolymerin and metalloproteinase (ADAMTS-4 and ADAMTS-5) containing platelet thrombin sensitive protein domain in chondrocytes was downregulated, and joint degeneration was delayed[26].

3.1.5 Salvia miltiorrhiza

“Day Hua Zi” said: “To treat cold and heat fatigue, joint pain,limb paralysis; Discharge pus pain relief, muscle broken blood,fill new blood “.The main active ingredients of salvia miltiorrhiza include tanshinone, cryptotanshinone, etc, which can promote blood circulation, remove blood stasis, relieve pain, cool blood and eliminate carbuncle.Tanshinone IIA decreased the proportion of apoptotic chondrocytes from 41% to 2%, inhibited ECM degradation, and inhibited the expression of interleukin-1β(IL-1β)and tumor necrosis factor (TNF-α) induced by iNOS activation.Reduce KOA inflammatory response[27].In vitro experiments showed that Tanshinone IIA could regulate the expression levels of Mir-155 gene and FOXO3 (FOXO3) in human articular chondrocytes,and improve KOA by inhibiting Mir-155 /FOXO3 axis, which further confirmed the anti-inflammatory and anti-apoptotic effects of tanshinone IIA[28].Feng et al.[29] found that cryptotanshinone can effectively prevent the destruction of cartilage and the thickening of subchondral bone in KOA mouse model, and inhibit the activation of mitogen activated protein kinase (MAPK) and NF-κB signaling to inhibit the production of a variety of inflammatory mediators, thus playing an anti-inflammatory role.

3.1.6 Other drugs for promoting blood circulation and removing blood stasis

In addition to more traditional Chinese medicines for promoting blood circulation and removing blood stasis in the above studies,some other medicines for promoting blood circulation have prevention and treatment effects on KOA.For example, the strychnos extract, total strychnos, can reduce the whole blood viscosity and plasma viscosity of KOA rats, promote blood circulation and reduce intraosseous pressure, thus improving the nutrient supply of cartilage[30].Leonurine can regulate the mitochondria-mediated apoptosis related factor B lymphocytoma-2 gene (Bcl-2)/ Bcl-2 related X gene (Bax)/cysteine-containing aspartic acid proteolytic enzyme 3(Caspase-3) apoptosis signaling pathway to inhibit chondrocyte apoptosis[31], and has good anti-inflammatory and antioxidant capacity.Can reduce the expression levels of various inflammatory factors and oxides in synovial tissues, and reduce synovial inflammation in KOA mice[32].Saffron can reduce joint pain in KOA rats by reducing the content of pro-inflammatory factors, and at the same time reduce oxidative stress response and improve muscle dysfunction[33].

In summary, there have been a large number of basic studies on the prevention and treatment of KOA by traditional Chinese medicines for promoting blood circulation and removing blood stasis.“Medical forest error correction” has cloud: “bi has yu blood”.Blood stasis is a pathological product that runs through the whole stage of genu bi,and is also one of the aggravating factors of the disease.It is caused by excessive strain, deficiency of qi and blood, combined with trauma and external evil invasion, resulting in poor blood flow, and blood stasis obstructs blood collaterals.Therefore, promoting blood circulation and removing blood stasis should run through the whole process of KOA treatment.The stasis and other pathological products deposited in the knee joint can be eliminated by the treatment of qi and blood circulation, aging and decay, and new blood and tissues can be generated at the same time, so as to play the role of removing blood stasis, generating new and smoothing joints[34].At present,drugs such as angelica sinensis, peach kernel, catechu catechu,caulis spatholobi and so on are commonly used in clinical treatment of KOA.For patients with a long course of disease, blood broken products such as turmeric turmeric and turmeric turmeric can be used appropriately.The mechanism of their treatment needs to be further explored.

3.2 Antipyretic

3.2.1radix rehmanniae recen

Catalpol rehmannium is a iridoid glycoside compound extracted from the root of rehmannium.It has anti-apoptotic and antiinflammatory effects[35].0 ～ 100μg/mL Rehmanniol showed no obvious toxicity to KOA rat chondrocytes, and could increase the contents of type ⅱ collagen and aggregate proteoglycan, and prevent the degradation of extracellular matrix (ECM)[36].Qiang He et al.[37]found that different concentrations of Rehmanniol could down-regulate the expression of calcium-binding protein (S100A12)and IL-1βin synovium tissues of KOA rats to inhibit the release of inflammatory factors, and reduce the content of Galecton-3 to slow the trabecular bone loss and bone strength reduction, and the effect was better in the high-dose group.In addition, catalpol can inhibit the activation of NF-κB pathway, reduce IL-1β-induced inflammation, catabolism and apoptosis of rat chondrocytes, and thus restore the function of chondrocytes[38].

3.2.2 Sophora

Sophora flavescens has the effect of clearing heat and dampness and diuresis.In vitro experiments showed that matrine could inhibit the expression of MMPs, an important enzyme involved in ECM degradation, by inhibiting the activation of MAPK and NF-κB signaling pathways in human chondrocytes, prevent the degradation of type ⅱ collagen and proteoglycan caused by the overexpression of MMPs, and significantly reduce the percentage of apoptosis of chondrocytes.These results suggested that matrine could inhibit ECM degradation and inhibit apoptosis[39].It was found that sophorine, another alkaloid of sophora sophora, inhibited PI3K/AKT/NF-κB signal transduction pathway, alleviated the contents of NO, prostatin E2(PGE2), cycx-2 (COX-2), iNOS and other proinflammatory factors, thus protecting the bone and joints[40].

3.2.3 Rhubarb

Rhubarb is a plant of polygonaceae.It is cold in nature and bitter in taste.It has the functions of clearing heat and reducing fire,cooling blood and detoxifying, promoting blood circulation and removing blood stasis.Emodin, an anthraquinone derivative derived from the rhizome of rhubarb, has a certain effect on delaying the degeneration of articular cartilage of KOA.It was found that 10, 20 and 30 μg/ mL of emdin significantly reversed 10 ng/ mL IL-1β induced chondrocytotoxicity in KOA rats, inhibited the activation of ERK and Wnt /β-catenin signaling pathways, down-regulated the expression of a series of inflammatory mediators in chondrocytes,and promoted the proliferation of chondrocytes[41].Another researcher injected emodin into the joint of KOA rats, and found that emodin inhibited the expression of MMPs and ADAMTS protein in a dosedependent manner, increased the expression of proteoglycan and type II collagen, decreased the occurrence of cartilage degradation, and played a protective role in articular cartilage[42].Rhubarb acid is also one of the active components of Rhubarb.The activity of NF-кB signaling in cartilage, the contents of IL-1β,iNOS and NO in serum, and the expression of synovium monoclonal antibody (ED1) and calcitonin gene-related peptide (CGRP) in synovium tissue of KOA macaques were decreased by rhuhuin et al using Hulth method.At the same time, the expression of cartilage type ⅱ collagen (COL2) was increased to achieve the therapeutic effect of KOA[43-44].

3.2.4 Golden buckwheat

Gold buckwheat has the effect of clearing away heat and detoxifying, discharging pus and removing blood stasis, and can be used to treat rheumatism and arashi syndrome, etc.The study found that the extract of Buckwheat can reduce the inflammatory reaction in the serum and joint fluid of KOA model rabbits and inhibit the apoptosis of chondrocytes[45].It can also increase the content of antioxidant enzyme SOD in the tissues of KOA model rats, reduce the contents of lipid peroxide (LPO) and malondialdehyde (MDA),and improve the metabolic balance of oxygen free radicals.Reduce damage to cartilage[46].

3.2.5 Other heat-clearing drugs

Studies have found that some antipyretic drugs have a certain effect on the treatment of KOA.For example, paeonol and dandelion sterol can reduce the content of various oxides to reduce oxidative stress response, thus alleviating the overexpression of inflammatory cytokines[47-48].In addition, gardenoside and artesunate also have anti-inflammatory effects on KOA.In vivo and in vitro experiments have shown that jasminoside inhibits the production of a variety of inflammatory mediators by inhibiting p38 mitogen-activated protein kinase (P38 MAPK) signaling pathway[49],Artesunate could improve synovial inflammation by downregulating the expression of angiogenic factors in KOA rat model[50].The results showed that total flavonoids of Baicalearia baicaleae could enhance the proliferation rate and reduce the apoptosis rate of chondrocytes by activating the type X collagen α1 chain (COL10A1)/ sexdetermined region Y-box protein 9(SOX9) signaling pathway[51].Li et al.[52] found that shikolin could down-regulate the expression of MMPs and up-regulate the expression of TIMP-1, that is, reduce the damage of matrix metalloenzymes to ECM by maintaining the balance between procartilage ECM catabolism and anabolism.

“The golden Want of the wings” said: “the heat of the heat, closed in the heat.” The acute phase or the middle and late stage of the disease is mostly characterized by damp and heat, local redness and swelling of the knee joint and heat pain, and the syndrome is damp and heat accumulation[53].According to traditional Chinese medicine, it is urgent to treat the symptoms, and slow to treat the root, so the main treatment should be to clear heat, detoxify and deswelling, in order to improve the knee function and the metabolism of local tissues, accelerate the absorption of inflammation, and relieve pain.The anti-KOA effects of the above heat-clearing agents have been confirmed in basic experiments, while the anti-koA effects of other heat-clearing agents need to be verified.

3.3 Antirheumatic drugs

3.3.1 Orientvine Sinomenine is an alkaloid monomer extracted from

Chinese herbal medicine, Sinomenine plays an anti-inflammatory,immunomodulatory and analgesic role in the treatment of KOA.The researchers speculated that the mechanism of action of sinomine lies in the down-regulation of mRNA and protein expression of TLR2, TLR4 and My D88 in the TLR/ myeloid differentiation factor 88(My D88) pathway, and the inhibition of cartilage immune response in KOA rabbits[54], On the other hand, inflammation and cartilage degradation can be reduced by reducing the levels of lipins and resistin in the articular cavity of KOA rabbits[55].In addition,sinomine can reduce the expression levels of VEGF and NGF, which are closely related to pain in cartilage and synovium of KOA rabbits,so as to improve pain behavior[56].

3.3.2 Siegesbeckia

Siegesbeckiae is often used in the treatment of gout arthritis,rheumatoid arthritis and other bone diseases, with the effects of rheumatism, joints and detoxification[57].Studies have shown that Herba Siegeskiae can inhibit il-1β, TNF-αand cartilage oligomaterials matrix protein (COMP) levels in serum of KOA rats by upregulation of sirt1 expression and down-regulation of FOXO1 acetylation, so as to reduce cartilage damage and improve joint swelling, pain and other clinical symptoms of KOA rats[58].Dong Hua et al.[59] found that extracts from Herba Juegeskieskiae could reduce MDA peroxidation level and increase SOD antioxidant level to inhibit oxidative overreaction in KOA rats, and also reduce the levels of NADH oxidase 2(NOX2)/ ROS /NF-κB pathway related molecules NF-κB, NOX2 MRNA and protein.Thus alleviating the damage of articular cartilage tissue in rats.

3.3.3 Fraxinus bungeana

Fraxinus bungeana beginning in the “Shennong Materia medica”,good at removing wind dampness, shu collateral, retreat deficiency heat, can be used for rheumatism pain, joint pain, muscle clonic syndrome.The results showed that gencholine, extract of Gentiana macropylana, had a significant therapeutic effect on KOA, which showed that the symptom of KOA rats’ foot swelling was reduced,the expression levels of IL-6, IL-1βand TNF-αin serum and joint fluid were decreased, and the synovial swelling and congestion were improved[60].Zhang Yanxia et al.[61] found that gentiopicrin in Gentiana macropylana could reduce the whole blood viscosity of KOA rats, inhibit the increased expression of PGE2, NO and COX-2 induced by il-1βin serum, and reduce the inflammatory response.

3.3.4 Other antirheumatic drugs

Daphthene and extracts of Atractylodes actylodes had good antiapoptotic effects on KOA chondrocytes.Daphnetin can inhibit the activation of PI3K/AKT, MAPK and NF-κB signaling pathways,reduce the ratio of BAX/ Bcl-2 in mitochondrial pathway of apoptosis, inhibit the expression of apoptotic factor Caspase-3, and reduce the occurrence of apoptosis[62].The extract of ATractylodes actylodes reduced the apoptosis rate of chondrocytes and promoted their proliferation by inhibiting the expression of Mir-378c gene in chondrocytes, up-regulating the expression levels of cyclin CyclinD1 and anti-apoptotic factor Bcl-2, and down-regulating the expression levels of cell cycle promoter P21 and pro-apoptotic factor Bax[63].Chen Xiaoyu et al.[64] found that triptolide could reduce the contents of C-Jun and MMP-9 in synovial tissue of KOA, inhibit the levels of PGE2 and IL-8 in peripheral blood, and play an anti-inflammatory role.The results showed that CHIropolysaccharides could downregulate the expression levels of abnormal oxygen free radical NO and MDA in chondrocytes, up-regulate the expression level of antioxidant enzyme SOD, enhance the ability of body to fight oxidative stress, and reduce the damage of oxidative response to bone cell membrane and intracellular mitochondrial structure[65].

Arthralgia theory says: “The so-called arthralgia, each in its time to feel the heavy wind cold wet also.” Ancient doctors all agree: due to the deficiency of the body, the human body is invaded by wind cold dampness and developed into arthralgia syndrome.Wind evil is the long of all diseases, causing cold and wet evil to invade the body,by wei biao fur muscle gradually into the joints and tendons.Knee joint is located in the lower part of the human body, more vulnerable to the invasion of evil, pain, numbness, severe symptoms.Based on this, wind dehumidification is the basic law of the treatment of KOA,common drugs such as wind, mulberry parasitic, live alone, looffa and other wind dredging collateral, dehumidification and pain relief.

3.4 Tonify deficiency

3.4.1 Fructus Lycii

Fructus Lycii has nourishing liver and kidney, benefit shrewd purpose effect.Lycium barbarum polysaccharide (LBP) is a high content component of Chinese medicine Fructus Lycii, which has antioxidant, hypoglycemic, immune regulation and other biological activities[66].The results showed that LBP at 100, 200, 400 and 800 μg/mL could promote the proliferation of chondrocytes for 24 h, and LBP at 400 μg/mL had the best proliferation effect.It can significantly reduce the expression of IL-1β,TNF-αand iNOS by inhibiting the activation of NF-κB signaling pathway, and upregulate the expression of anti-inflammatory and tissue repair factor TGF-β, exerting anti-inflammatory effect[67].In addition, LBP can inhibit the high expression of CD151 gene and MMP-3 in KOA rabbit cartilage tissue, and effectively reduce the content of MMP-3 through the positive promotion of CD151 on MMPs, and delay the degeneration of articular cartilage[68].

3.4.2 Epimedium

Epimedium has the effect of tonifying kidney Yang, strengthening muscles and bones, and eliminating wind dampness.It is widely used in clinical treatment of joint pain, muscle and bone Microsoft syndrome.Icariin is a Chinese medicine monomer isolated from epimedium.The results showed that 0 ～ 20 μM icariin had NO toxicity to CHONdrocytes induced by TNF-α, enhanced cell viability, significantly reduced il-1, IL-6 and IL-12, exerted antiinflammatory effect, inhibited the expression of NO and ROS, and reconstructed the metabolic homeostasis of cartilage.The results showed that the percentage of S phase cells increased from 22.27%to 26.11%, and the cell death ratio decreased from 46.33% to 24.33%, indicating that icariin could promote the normal division of chondrocytes and reduce the apoptosis rate.In addition, icariin can activate autophagy in chondrocytes, up-regulate the expression levels of autophagy markers Atg 5, Atg 7 and LC3-II, and further inhibit the inflammatory response[69].He et al.[70] found that icariin could inhibit the expression of VEGF and HIF-1 in peripheral blood of KOA rats by regulating TDP-43 signaling pathway, prevent the formation of new blood vessels in synovial tissue, and improve the local microcirculation of knee joint.

3.4.3 Astragalus

Astragalus is one of the most commonly used drugs for the treatment of KOA.Astragalus mainly contains saponins,polysaccharides, flavonoids and other components, and its different pharmacological activities have different emphasis in the treatment of KOA.It was found that astragaloside IV inhibited the production of various inflammatory factors in chondrocytes induced by IL-1βin a dose dependent manner, and reduced the inflammatory response[71], It can reduce the expression of Wnt/β-catenin signaling pathway related factors MMP-7, c-terminal peptide of typeⅱcollagen (CTX-ⅱ) and COMP in synovial tissue,inhibit the degradation of cartilage matrix, and improve synovial inflammation[72], It regulates the expression level of MMP metal degrading enzymes to reduce their damage to the extracellular matrix of cartilage and delay cartilage degeneration[73].In addition,ASTRagaloside IV reduced IL-1β-induced chondrocyte apoptosis through autophagy activation[74].Total flavonoids of Astragalus membranaceus is an active antioxidant component extracted from Astragalus membranaceus.It can inhibit the activation of NF-κB signaling pathway, reduce the expression of oxidative stress and inflammation-related factors in KOA chondrocytes, and play an antioxidant and anti-inflammatory role[75].

3.4.4 Other deficiency tonic

Tonifying deficiency drugs have the effect of tonifying deficiency loss and enhancing immune ability, and can play the role of promoting chondrocyte proliferation, anti-inflammatory and analgesic in treating KOA.For example, salidroside promotes chondrocyte proliferation in KOA rats and alleviates cartilage degeneration by reducing collagen fibrosis and regulating inflammatory and immune responses through the NF-κB pathway[76].Psoralen promotes chondrocyte proliferation by increasing the expression levels of key proteins in the Wnt/β-catenin signaling pathway of chondrocytes, which is manifested in the increased expression levels of Wnt-4, β-catenin and cyclin D1[77].In some experiments, saffrine O staining was used to observe that the extract of Fructus lucidum also promoted the proliferation of chondrocytes in KOA rats, and improved their arrangement and collagen quality.At the same time, the expression of collagen type 10 (Col10) and MMP13 was down-regulated, and the expression of collagen type 2 (Col2) and cartilage matrix gene proteoglycan(Aggrecan) was up-regulated, and chondrocyte hypertrophy and catabolism were inhibited to improve KOA pain[78].It was found that a variety of tonic drugs had a good anti-inflammatory effect on KOA,such as gynostemma pentaphylus saponin inhibits the production of various inflammatory factors by inhibiting the activation of NF-κB signaling pathway, and has a protective effect on cartilage tissue[79]9.In addition, water extracts of Eucommia ulmoides[80], Fructus corni neoside I[81]and other compounds have also been proved to inhibit inflammatory response by reducing the content of MMP family, interleukin-family and other related inflammatory factors.

The ancients said: “liver main gold, kidney bone”, “kidney bone marrow, liver marrow.”It shows that the normal activities of joints and bones are closely related to the joint effect of liver and kidney.The kidney essence is sufficient, the liver and blood are filled, and the bones and muscles can be nurtured.KOA usually occurs in the middle and old age, because the kidney essence of the human body is in the stage of decline, the deficiency of blood is not enough to nourish the muscles and bones of the knee, and the knee is impotent and weak, pain, and adverse flexion and extension symptoms.Therefore, tonifying liver and kidney, supplementing qi and nourishing blood are the key ideas of treating KOA.Kidney Yin is insufficient, can not nourish muscles and bones, commonly used drugs such as dendrobium, tortoise shell, such as nourishing Yin kidney bone; Deficiency of kidney Yang, loss of muscles and veins in warm, commonly used drugs such as psoralea, cistanche, such as kidney and Yang.

3.5 Other Traditional Chinese medicines

In addition to the above four traditional Chinese medicines, there are other kinds of traditional Chinese medicines that have certain therapeutic effect on KOA.For example, zanthoxylenol inhibits the activation of NLRP3 protein in inflammasome and down-regulates NF-κB signaling pathway, thereby inhibiting inflammatory response[82].The anti-inflammatory effect of puerarin has also been confirmed.Some scholars found by ELASA detection that puerarin can down-regulate the expression of inflammatory factors TNF-α,IL-6 and IL-12 in a dosi-dependent manner, and can reduce the inflammatory infiltration of blood monocytes in human body[83].Osthole inhibits IL-1β-induced cartilage inflammation by inhibiting THE PI3K/AKT/NF-κB pathway, which is a downstream signaling target[84].In addition, the anti-inflammatory effect of SCHisandra chinensis extract on KOA was achieved by inhibiting the activation of MAPK and NF-κB signaling pathways[85].The enhancement of cyclin D1 expression can promote cell proliferation.Allicin can accelerate the cycle of chondrocytes by upregulating cyclin D1 expression and downregulating the expression of cyclin related protein P27[86].

5.Discussion and prospect

Traditional Chinese medicine has broad application prospect in the prevention and rehabilitation of KOA.Compared with the traditional KOA clinical efficacy evaluation system, the use of PCR technology,immunohistochemistry and other modern medical technologies were used to detect the related biological factors, which made the evaluation of the efficacy of TRADITIONAL Chinese medicine on KOA more accurate.Based on this paper, the mechanism of action of traditional Chinese medicine on KOA was summarized,and the author found (1) The active ingredients such as flavonoids,glycosides, phenols, terpenoids and other active components of most traditional Chinese medicines for promoting blood circulation and removing blood stasis, clearing heat, eliminating wind dampness,reinforcing deficiency and a few other traditional Chinese medicines can inhibit inflammation, resist oxidative stress, regulate the balance of cartilage metabolism, improve local microcirculation,play an analgesic role, and effectively improve the occurrence and development of KOA.Therefore, it is feasible to treat KOA with traditional Chinese medicine by activating blood circulation and dredging collateral, eliminating wind and dehumidification, and supplementing liver and kidney.(2) Some Chinese medicines,such as turmeric, epimedium, rhubarb can apply to multiple signal pathways to interfere with KOA, It can be seen that different signal pathways cooperate and influence each other in related mechanisms of action to jointly maintain the normal physiological functions of cells and the local microstructure of the knee joint, which fully proves that Chinese medicine in the prevention and treatment of KOA possesses the advantages of multiple targets, way.(3) At present, the basic studies on the treatment of KOA with Traditional Chinese medicine are mostly based on NF-κB, MAPK, PI3K/Akt,Wnt/β-catenin pathways and the exploration of individual target proteins, while there is a lack of literature on the exploration of TGFβand Toll-like receptor signaling pathways and axin.

Although there are many researches on the prevention and treatment of KOA with traditional Chinese medicines, there are still certain limitations: the lack of the cell toxicity and bioavailability of Chinese traditional medicine research and application in clinic, limiting its,still need to use more widely in the future, advanced technology,fully excavate the pharmacological effects of Chinese medicine,and large sample, multicenter basic research, clinical practicability.In view of the existing research lack of water wet, remove blood stasis phlegm, qi blood tonic medicines research question, the future can be combined with bioinformatics methods, such as the network pharmacology screening, assessment of traditional Chinese medicines can be used in the treatment of KOA more, and pay attention to how to use a variety of traditional Chinese medicine to regulate multiple signaling pathways to regulate the progression of KOA.At the experimental level, most of the existing studies are animal experiments or cell experiments, lacking an experimental models combining disease and syndrome, which cannot fully verify the theory of TCM treatment of KOA.Therefore, how to integrate the thought of TCM “syndrome differentiation and treatment” into the experiment with modern medical technology will be needed to be considered and improved in the future.In this paper, the mechanism of action of Traditional Chinese medicine in the prevention and treatment of KOA was summarized, and the research status of the application of traditional Chinese medicine in KOA at home and abroad in the past five years was clarified.In the future, we need to continue to develop and study more traditional Chinese medicine for KOA, in order to provide scientific theoretical basis for clinical application.

Description of author contribution:

Qin Shu-ying: Article ideas and writing

Wei Cheng-yu,Li Liu-zhen: Explore Literature

Chen Zhi-fen,Liu Yong-li: Organize documents

Su Jing: Provide guidance

Lei Long-ming: Check the quality of articles and provide ideas, as well as authenticity, feasibility.