Research Progress On The Regulation Of NF-κB Signaling Pathway By Active Components Of Traditional Chinese Medicine in The Treatment Of Knee Osteoarthritis

［Abstract］ KOA is a degenerative disease mainly affecting middle-aged and elderly people. Its pathological characteristics are articular cartilage injury, marginal osteophyte formation, and the occurrence of inflammation, etc., which are usually manifested by joint pain and limited movement in clinical practice. At the same time, KOA can cause joint deformities due to its limited movement, making it impossible to walk normally, causing serious economic burden to patients' families. Previous studies have found that the pathogenesis of KOA is closely related to inflammation and the metabolism of chondrocytes. In recent years, with the in-depth research at home and abroad, it has been found that the nuclear transcription factor-κB (NF-κB) signaling pathway is involved in the inflammation and metabolism of chondrocytes, and can improve bone metabolism and bone microstructure by regulating the generation of inflammation and proliferation of chondrocytes, and plays a crucial role in the prevention and treatment of KOA. In addition, traditional Chinese medicine has a long history of prevention and treatment of KOA, outstanding efficacy, few adverse reactions, and has the characteristics of multiple targets, wide sources, and economic suitability. In order to provide a reasonable theoretical basis for clinical prevention and treatment of KOA, this article reviewed the latest research progress of regulating NFκB signaling pathway at home and abroad in recent years.

［Keywords］Traditional Chinese medicines monomer; The nf-kappa B sig naling pathway; Knee osteoarthritis(KOA); Mitogen activated protein kinase (MAPK) signaling pathway; Phosphatidylinositol 3-kinase (PI3K)/protein k inase B(Akt)/nf-kappa B signaling pathway;

HERB CISTANCHE FOR TREATMENT OF KNEE OSTEOARTHRITIS

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Knee osteoarthritis (KOA) is a disease that is common in the elderly. The incidence rate increases with age[1]. According to surveys, the probability of people over 60 suffering from KOA can reach 30%~50%[2]. Long-term load and biomechanical changes in the knee joint will aggravate the destruction of articular cartilage[3]. The main pathological changes are joint inflammatory reaction, cartilage damage and subperiosteal bone hyperplasia. Early clinical manifestations include knee pain, swelling, and limited movement. In the late stage, muscle atrophy and knee deformity may occur[4,5].

In recent years, with the development of medicine, KOA has a more systematic treatment. In the early stage, anti-inflammatory drugs are mainly used to relieve symptoms[6]. This leads to multidrug resistance and adverse reactions. Therefore, it is urgent to develop more safe and effective drugs with outstanding efficacy, fewer adverse reactions, and easier for patients to accept. Traditional Chinese medicine has unique advantages in treating KOA. It uses the characteristics of traditional Chinese medicine to differentiate syndromes and treat them according to syndrome types (dampness and cold obstruction type, dampness and heat obstruction type, qi and blood stasis type, liver and kidney deficiency type, qi and blood weakness type, etc.) [5]. In recent years, many Chinese patent medicines (Hulisan Capsules, Zhuanggu Joint Capsules, Xianling Gubao Capsules, etc.) have been developed for the treatment of KOA [7]. Traditional Chinese medicine has the advantages and characteristics of a long history and outstanding efficacy. Traditional Chinese medicine believes that the liver stores blood, the liver is responsible for promoting the distribution of blood essence in the body, the liver is in the body to bind tendons, the kidney is responsible for bone production, and the liver and kidney are of the same origin. Therefore, traditional Chinese medicine promotes the regeneration of chondrocytes by nourishing the liver and kidneys, strengthening tendons and bones, promoting blood circulation, and regulating the distribution of blood in chondrocytes [8]. At the same time, the NF-κB signaling pathway stimulates the production of various proinflammatory cytokines (such as tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]), which is closely related to the progression of KOA [9]. The NF-κB signaling pathway participates in the survival, apoptosis and inflammatory response of KOA chondrocytes through these factors[10]. This article briefly summarizes the treatment of KOA by Chinese herbal medicine monomers through regulating the NFκB signaling pathway by reviewing the latest research reports at home and abroad in recent years, in order to provide a theoretical basis for the clinical treatment of KOA.

1 NF-κB signaling pathway and KOA

During the pathogenesis of KOA, the destruction of articular cartilage and the generation of inflammatory response are the main causes. The proinflammatory effect of inflammatory factors plays an important role in KOA joint damage. Inflammatory factors can accelerate the rate of cartilage damage[11]. The inflammatory response of KOA is mainly caused by inflammation of the synovial membrane in the joint[12]. As the inflammation intensifies, it will eventually lead to the destruction of articular cartilage and aggravate the patient's knee pain symptoms. Once the inflammatory factors spread to other joints, they will cause an inflammatory response of the synovial tissue in the joint[13], causing cartilage damage and aggravating the degree of wear between joints. Previous studies have found that the matrix metalloproteinase family (MMP) regulates the development of KOA and participates in the degradation of the extracellular matrix (ECM). Several inflammatory-related factors (IL-1β, TNF-α, etc.) in the synovial fluid can activate MMP-1 and MMP-3 to participate in the degradation of ECM[14].

NF-κB protein complex participates in chondrocyte apoptosis, inflammatory response and other processes in KOA. The activation of the NF-κB signaling pathway is closely related to the production of various inflammatory cytokines and mediators, such as TNF-α and IL-1β[15]. By inhibiting the signal transduction of p65/NF-κB, the levels of IL-6, IL-1β, and TNF-α can be downregulated, effectively preventing and treating the occurrence of KOA. At the same time, inhibiting the NF-κB, MAPK, and NFATc1 signaling pathways can weaken osteoclast formation and bone resorption, thereby delaying the progression of KOA[16], and finally achieving the purpose of promoting bone formation, increasing bone strength, improving bone microstructure, and preventing and treating KOA.

1.1 NF-κB/MAPK (mitogen-activated protein kinase) signaling pathway and KOA

The NF-κB/MAPK signaling pathway plays an extremely important role in the pathogenesis of KOA. NFκB is a classic inflammation-related pathway. Its activation increases the release of proinflammatory cytokines related to osteoarthritis[17]. By downregulating the levels of TNF-α, IL-6, and IL-1β, the phosphorylation level of NF-κBp65 in cartilage tissue can be reduced. NF-κB can induce the expression of prostaglandin 2 (PGE2), nitric oxide synthase (INOS), nitric oxide (NO), and cyclooxygenase-2 (COX2) to aggravate articular cartilage damage and trigger an inflammatory response[18]. At the same time, the activation of p38MAPK is also involved in the process of chondrocyte apoptosis. Y et al.[19] found that inhibiting the activity of p38 MAPK can weaken chondrocyte apoptosis caused by sodium nitroprusside (SNP) stimulation. By downregulating the p38/ERK MAPK, P38MAPK-related proteins, and p65/NF-κB signaling pathways, it is possible to prevent inflammatory responses, partially prevent cartilage degeneration, and prevent the progression of KOA[20]. By regulating the MAPK and PI3K/Akt signaling pathways, it is possible to inhibit the NF-κB signaling pathway and downregulate the protein levels of IL-6, IL-1β, and TNF-α, which is of great significance for the prevention and treatment of KOA.

1.2 Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/NF-κB signaling pathway and KOA

IκB-ζ is a subtype of NF-κB. IκB-ζ is essential for the expression of inflammatory factors such as IL-6 in chondrocytes[21]. AKT is a downstream target of PI3K. It plays a key role in cell proliferation and transcriptional cell processes, and has a regulatory effect on the release of inflammatory cytokines in organisms under oxidative stress[22]. Increased AKT signal transduction can inhibit the production of inflammation and is closely related to NF-κB. The PI3K/Akt signaling pathway can promote the phosphorylation of NF-κB and aggravate the inflammatory response[23]. Activation of the PI3K/Akt/NF-κB signaling pathway will aggravate the occurrence of cartilage inflammatory response[24]. Activated NF-κB p65 can promote the transcriptional expression of target genes such as IL-10, IL-6 and TNFα, leading to inflammation[25]. Inhibiting the expression of the TLR4-PI3K-Akt-NF-κB signaling pathway can prevent the occurrence of inflammatory response[26]. By inhibiting the activation of the PI3K/AKT/NF-κB signaling pathway, the occurrence of inflammatory response induced by IL-1β in chondrocytes was effectively weakened, effectively preventing the occurrence of KOA[27].

In addition to the two major NF-κB-related signaling pathways mentioned above, there are also miR-124/NF-kB signaling pathways[15], Nrf2/HO-1/NF-kB signaling pathways[11], NF-κB/activated protein kinase (AMPK) signaling pathways[28], Wnt/β-catenin and NF-κB signaling pathways. All of these pathways can regulate the activity of synovial cells, osteoblasts and chondrocytes in the knee joint and play an important role in the prevention and treatment of KOA[29].

The above NF-κB-related signaling pathways play an important role in the prevention and treatment of KOA by participating in the metabolism of chondrocytes, the expression of inflammatory factors and matrix proteins.

From the above, it can be seen that the NF-kB-related signaling pathway participates in the metabolism of chondrocytes by regulating inflammatory factors related to chondrocytes, and then participates in the occurrence and development of KOA. Therefore, using NFkB-related signaling pathways as targets can effectively inhibit the expression of inflammatory factors, effectively reverse pathological changes such as chondrocyte damage, and is the key target and pathway for the prevention and treatment of KOA in the future. It also provides a reliable theoretical basis for the development of more drugs that can effectively prevent and treat KOA.

2. The active ingredients of traditional Chinese medicine regulate NF-kB related signaling pathways and effectively prevent and treat KOA.

2.1 NF-κB/MAPK signaling pathway

2 1.1 Dihydroartemisinin

Ding et al. [16] experimentally found that in KOA rats, 5 μmol/L dihydroartemisinin (DHA) could significantly inhibit the levels of NF-κB, p-p38, p-JNK, and p-ERK1/2. Expression, the above three factors (ERK, JNK and p38) are protein kinases related to the MAPK signaling pathway and play an important role in bone metabolism. It is confirmed that DHA can inhibit the activation of T cell cytoplasmic nuclear factor 1 (NFATc1), NF- κB and MAPK signaling pathways to inhibit RANKL-induced osteoclastogenesis. Downregulate the phosphorylation levels of ERK, JNK and p38, increase cartilage protection, reduce osteoclast production, and increase bone content to prevent KOA. Prevent KOA by increasing cartilage protection, reducing osteoclast production, and increasing bone mass.

 2 1.2 Steviol glycosides

Cai et al. [30] experimentally found that steviol glycoside (SVS) reduced the phosphorylation of IκB and p65, inhibited IL-1β-stimulated JNK, p38 and p-ERK by down-regulating the expression of p-JNK, p-p38 and p-ERK in chondrocytes. ERK/MAPK signaling pathway. In addition, SVS also inhibits inflammation by down-regulating the expression of pro-inflammatory factors INOS, IL-6, TNF-α and COX-2. In terms of apoptosis, SVS increases the level of anti-apoptotic gene Bcl2. Increase, the level of pro-apoptotic gene BAX decreases, down-regulates the level of caspase-3, and alleviates chondrocyte apoptosis. This suggests that SVS prevents and treats KOA by mediating the MAPK/NF-κB signaling pathway.

2 1.3 Rupine

Wan et al. [31] experimentally found that in terms of inflammation, rupine (RUT) down-regulated the mRNA expression of IL-6 and TNF-α, and in terms of cartilage metabolism, RUT reduced PI3K/Akt/NF-κB in mouse chondrocytes. and the phosphorylation levels of p38, ERK1/2 and JNK, reducing the production of catabolic enzymes (MMP3 and MMP13) and inhibiting cartilage decomposition. At the same time, it upregulates the levels of COLII, aggrecan and SOX9, which is important for maintaining cartilage extracellular matrix ( ECM) stability also plays a key role. In terms of apoptosis, RUT prevents chondrocyte apoptosis by upregulating BCL2 and downregulating the expression of BAX. RUT plays a role in preventing and treating KOA through anti-inflammatory and anti-catabolism, promoting anabolism, and anti-apoptosis.

2 1.4 Quercetin

Qiao et al. [32] experimentally found that quercetin (QCT) inhibited the inflammatory response and ECM degradation in chondrocytes by down-regulating the protein expression of NF-κB, enhanced the glucose transport capacity in chondrocytes, and promoted chondrocyte regeneration, confirming that QCT plays an important role in preventing and treating KOA by inhibiting the NF-κB signaling pathway.

2 1.5 Formononetin

Xu et al. [33] experimentally found that using different doses of formononetin to culture lactating maternal mouse cells reduced MMP-13, TNF-α, IL-6, p-ERK/ERK, p-JNK/JNK, p -Protein expression of p38/p38, p-IκBα/IκBα, and p-p65/p65, which indicates that formononetin inhibits inflammation, reverses cartilage damage, and maintains the balance of cartilage matrix metabolism by regulating the MAPK/NF-κB signaling pathway. The purpose of preventing and controlling KOA.

2 1.6 Baicalin

Yang et al. [34] found that baicalin (SCU) can downregulate the mRNA levels of MMP3, MMP9, MMP13, a disintegrin metalloproteinase (ADAMTS4) and ADAMTS5 in KOA mice, thereby reducing the loss of ATDC5ECM. After SCU treatment, articular cartilage degeneration was significantly improved, and the bone volume fraction (BT/TV), trabecular thickness (Tb.Th) and trabecular number (Tb/N) of the ovariectomy (OVX) group were improved, which improved bone metabolism and reversed the degradation of ECM. At the same time, SCU regulated the NF-κB/MAPK signaling pathway by downregulating the expression of p-p38, p-JNK and pERK, p-IκBα, p-p65 and p-IKKα, thereby preventing the occurrence of KOA inflammation.

2 1.7 Curcuminol

Yang et al. [35] found that curcuminol can downregulate the expression of MMP3, MMP13, ADAM metallopeptidase and ADAMTS5 in mice to prevent the degradation of chondrocytes. At the same time, after treating ATDC5 cells with different concentrations of curcuminol, it was found that it downregulated the expression levels of p-P65, p-IκBα, p-SAPK/JNK, TNFα, and IL-1β, thereby alleviating the inflammatory response of KOA cartilage.

2 1.8 Caragana root extract

Min et al. [17] experimentally confirmed that in terms of chondrocyte metabolism, Caragana root extract can downregulate the protein expression of ERK, JNK, p38, NF-κB, the phosphorylation level of IκBα and the activity of catabolic enzymes (MMP-1, MMP-3, MMP-9, MMP-13) in OA rats, increase the expression of aggrecan, type II collagen and SOX-9, thereby inhibiting chondrocyte degradation and increasing ECM synthesis. In terms of inflammation, Caragana root extract downregulated the levels of COX-2, PGE2, iNOS and NO to inhibit the occurrence of inflammation. This shows that Caragana root extract can alleviate cartilage degradation and reduce the production of inflammatory mediators by regulating the NF-κB/MAPK pathway, thereby preventing and treating the occurrence of KOA.

2 1.9 Indigo carmine

Wang et al. [36] experimentally confirmed that the use of indigo carmine in OA mice inhibited the activation of NF-κB and MAPK signaling pathways, downregulated the expression of INOS and COX-2, inhibited the production of MMP3 and MMP13 induced by IL-1β, effectively reversed chondrocyte damage, and inhibited the production of inflammation to achieve the purpose of preventing and treating KOA.

2 1.10 Theaflavin-3,3'-dicarboxylate (TFDG)

Teng et al. [37] found that theaflavin-3,3'-dicarboxylate (TFDG) can downregulate the protein expression of ERK, p38, JNK, and NF-κB in OA rat chondrocytes. In addition, it can inhibit the expression of inflammatory mediators such as IL-1β, PGE2, IL-6, and TNF-α, reduce the expression of matrix degrading enzymes (MMP13, MMP3, and ADAMTS5), and protect the ECM components of chondrocytes, proving that TFDG can regulate NF-κB and MAPK signaling pathways to prevent KOA.

2 1.11 Hyperoside

Sun et al. [38] experimentally confirmed that after hyperoside was applied to OA mice, the expression of INOS, COX2, MMP3 and MMP13 decreased significantly, effectively alleviating the decrease in the expression of collagen II, aggrecan and SOX9 induced by IL-1β, and inhibiting the degeneration and degradation of cartilage. In addition, hyperoside also inhibited the phosphorylation of NF-κB p65 and IκBα induced by IL-1β, inhibited the signal transduction of NF-κB by increasing the protein expression of Nrf2 and HO-1, and also downregulated the expression of ERK and JNK, inhibited chondrocyte inflammation and promoted the synthesis of chondrocytes. It was confirmed that hyperoside inhibited the inflammatory response and chondrocyte degradation by regulating the NF-κB and MAPK signaling pathways, thereby playing a role in preventing and treating KOA.

2 1.12 Schisandrin A

Han et al. [39] found that after schisandrin A was applied to OA mice, it blocked IκB degradation and p38 and JNK phosphorylation to inhibit the activation of NF-κB and MAPK signaling pathways, thereby inhibiting the occurrence of KOA mechanism. In addition, it reversed the damage of chondrocytes by reducing the levels of MMP3 and COX-2.

2 1.13 Ginsenoside-Rb1

Hossain et al. [40] found that ginsenoside-Rb1 acted on OA rabbit models, preventing cell apoptosis by inhibiting the production of intracellular reactive oxygen species (ROS), and down-regulated the expression of MMPs and apoptosis markers TNF-α, caspase3 and bax. NF-κB and P38MAPK signaling pathways were inhibited by ginsenoside-Rb1, which played an inhibitory role in the pathogenesis of KOA.

From the above results, it can be seen that the NF-κB/MAPK signaling pathway plays an important role in the occurrence and development of KOA. On the other hand, many Chinese herbal extracts prevent and treat KOA by regulating the NF-κB/MAPK signaling pathway. In addition, the efficacy of Chinese herbal extracts such as dihydroartemisinin, stevioside, and hyperoside in the prevention and treatment of KOA has been found. This means that the NF-κB/MAPK signaling pathway is a target and pathway for more and more effective prevention and treatment of KOA in the future.