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Potential Advantages of Bioactive Compounds Extracted From Traditional Chinese Medicine to Inhibit Bone Destructions in Rheumatoid Arthritis

Bone destruction is an important pathological feature of rheumatoid arthritis (RA), which finally leads to the serious decline of life quality in RA patients. Bone metabolism imbalance is the principal factor of bone destruction in RA, which is manifested by excessive osteoclast-mediated bone resorption and inadequate osteoblast-mediated bone formation. Although current drugs alleviate the process of bone destruction to a certain extent, there are still many deficiencies. Recent studies have shown that traditional Chinese medicine (TCM) could effectively suppress bone destruction of RA. Some bioactive compounds from TCM have shown good effect on inhibiting osteoclast differentiation and promoting osteoblast proliferation. This article reviews the research progress of bioactive compounds exacted from TCM in inhibiting bone destruction of RA, so as to provide references for further clinical and scientific research.


INTRODUCTION
Rheumatoid arthritis (RA) is a erosive autoimmune condition with lingering course (Smolen et al., 2016). Bone destruction is one of the most typical pathological features in the early RA patients, more than 10% of patients will occur pathological manifestation 8 weeks after onset (Panagopoulos and Lambrou, 2018). Current drugs for the treatment of RA are mainly non-steroidal antiinflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs (DMARDs), hormones, biological agents and so on. Although these drugs alleviate the process of bone destruction to a certain extent, the long-term use is easy to produce side effects. Therefore, further scientific research on the treatment of bone destruction is still urgently needed. As is known to all, traditional Chinese medicine (TCM) has been used to treat RA for centuries and shown good efficacy (Guo Q. et al., 2017;Zhang Q. et al., 2019;. Recently, accumulating evidence have indicated that bioactive compounds extracted from TCM can effectively inhibit osteoclast differentiation as well as promote osteoblast proliferation, and may be used as potential therapeutically drugs. Therefore, this paper aims to review the potential therapeutic effect and targets of some representative bioactive compounds extracted from TCM, in order to provide reference for future research and development.

BONE METABOLISM IMBALANCE IS THE KEY TO BONE DESTRUCTION IN RA
Bone is a metabolically active organ that keeps alive through continuous renewal in the process of bone remodeling. Bone remodeling depends on the balance between bone formation and bone resorption that maintains the homeostasis of bone reconstruction (Lian, 2015). Bone destruction in RA mainly lies in excessive bone absorption and insufficient bone reconstruction. Osteoclasts play an important role in bone resorption; they are derived from monocyte/macrophagelineage hematopoietic precursor cells which are stimulated by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL) (Fujiwara et al., 2016). Mature osteoclasts can express proteins including integrin, artrat resistant acid phosphatase (TRAP), calcitonin receptor (CTR), cathepsin K (CTSK), and matrix metalloproteinase (MMP) at the bone surfaces that are infiltrated by synovial cells (Zhu et al., 2020a). Osteoclast differentiation is a complex multistep process, and its molecular mechanism mainly involves the regulation of inflammation mediators, transcription factors, and signal pathways. Inflammatory mediators including tumor necrosis factor-alpha (TNF-a), interleukin-1 beta (IL-1b), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-17 (IL-17), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), etc., can promote the augment of RANKL and M-CSF after binding to the receptors on osteoclasts, so as to aggravate bone resorption in RA. Simultaneously, the initiation of osteoclast differentiation in the process of bone destruction in RA also needs the regulation of transcription factors including nuclear factor of activated T cells (NFATc1), cellular oncogene fos (c-fos), cellular oncogene jun (c-Jun) (Zhu et al., 2020a). These cytokines mediate the regulation of osteoclasts on bone destruction in RA through multiple signal pathways. For instance, TNF-a and other pro-inflammatory cytokines secreted by synoviocytes and T cells in RA promote osteoclast differentiation by activating nuclear factor kappa-B (NF-kB), mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator (JAK/STAT), hypoxia inducible factor-1a (HIF-1a), phosphatidylinositol-3 kinase/protein-serinethreonine kinase (PI3K/AKT), Toll-like receptor (TLR), etc. In-depth understanding of the pathological process of osteoclasts in RA, monitoring and interfering with the cytokines and signal pathways that promote osteoclast activation can provide a new target for the treatment of bone destruction in RA.
The occurrence of bone destruction in RA is not only the reason of the enhancement of bone resorption mediated by osteoclasts, but also due to the limited bone formation (bone repair) mediated by osteoblasts (Gravallese, 2017). Osteoblasts participate in osteoclasts regulation by expressing RANKL and OPG (Corrado et al., 2017). Bone marrow mesenchymal stem cells (BMSCs) are the main source of osteoblasts, BMSCs is a kind of stem cells with the potential of self-proliferation and multi-directional differentiation, which can differentiate into bone, cartilage, muscle, and other tissues under the action of different environments and stimulating factors (Komori, 2010). Because of the stimulation of cytokines such as insulin-like growth factor 1 (IGF-1) and transforming growth factor-b (TGF-b), BMSCs differentiate into osteoblast progenitor cells under the regulation of transcription factors such as Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein-2 (BMP-2) (Blair et al., 2017;Komori, 2019). Subsequently, osteoblasts form osteoid, and mature osteoblasts highly express calcification-related proteins, which are mainly osteocalcin (OCN), bone morphogenetic protein-2 (BMP-2), and osteopontin (OPN) (Blair et al., 2017;Halling Linder et al., 2017;Komori, 2019). At the same time, Wnt/b-catenin, BMP/ Smad, and Notch signaling pathways will act on osteoblast differentiation and maturation. Sclerostin and dickkopf-related protein 1 (Dkk-1) are the Wnt/b-catenin signaling pathway inhibitors which prevent low-density lipoprotein receptorrelated protein 5/6 (LRP 5/6) from binding to downstream signal receptor. Studies have found the expression of Wnt/b-catenin signal pathway inhibitors in osteoblasts of patients with RA was increased, which inhibited the activity of osteoblasts and promoted osteoblast apoptosis, and TNF-a and IL-1 played a promoting role (Miao et al., 2013). BMP/Smad signaling pathway can promote the formulation of osteoblasts by regulating all aspects of osteoblast cycle and has a synergistic effect with Wnt/ b-catenin signaling pathway (Dejaeger et al., 2017). Miyazono et al. found that both osteoblast development and osteoblast function in BMP2/4 knockout mice were defective, and the number of osteoblasts decreased, all of which might be caused by the down-regulation of Runx2 and Osx (Miyazono et al., 2010). Verschueren et al. have proved that the total amount of phosphorylated Smad1 and Smad5 in synovium of patients with RA increased significantly compared with the control group (Verschueren et al., 2009). Many kinds of cytokines and signal pathways are interlaced with each other, and the correlation is complicated in bone metabolism. Therefore, it is the key to treat bone destruction in RA by regulating the balance between osteoclasts and osteoblasts.
bone destruction has become one of the main strategies for the treatment of RA. The treatment guidelines recommend the use of methotrexate (MTX) or biological disease modifying antirheumatic drugs (bDMARDs) first when bone destruction is found (Singh et al., 2016;Smolen et al., 2017). Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) is regarded as the cornerstone in the treatment of RA, and it is also a first-line drug recognized by domestic and foreign guidelines (Singh et al., 2016;Smolen et al., 2017). This type of drug can effectively control the development of the disease, improve the clinical symptoms of RA and prevent the continued destruction of joint structure, but the therapeutic effect is relatively slow and it is not effective in all patients with RA (Schett et al., 2016). Glucocorticoids have strong antiinflammatory and immuno-suppressive effects, short-acting hormones are used in the treatment of acute stage of RA (Güler-Yüksel et al., 2018). low-dose glucocorticoid can quickly relieve joint swelling and prevent joint bone destruction (Tada et al., 2016). However, unreasonable long-term use of glucocorticoids can lead to a decrease in bone mineral density and an increase in the risk of fractures (Zerbini et al., 2017;Güler-Yüksel et al., 2018). The emergence of bDMARDs can be said to be a breakthrough in the treatment of bone destruction in RA and bDMARDs have clear targeting in the treatment of bone destruction (Aletaha and Smolen, 2018). The main function of it is to antagonize the activities of T cells, B cells, osteoclasts, cytokines, and some small molecules, which delay bone destruction (Ho et al., 2019). Although the bDMARDs can correct the abnormal bone metabolism of patients to a certain extent, and improve their imaging examination and serum bone metabolism indexes, high costs reduce the dose, or frequency of bDMARDs (Burmester and Pope, 2017). In addition, they are not suitable for the complex conditions of all patients because of the single target (Zampeli et al., 2015). In summary, the current clinical application of drugs cannot adequately prevent the bone destruction in all RA patients. Due to the complexity of the bone destruction mechanism in RA, we need to explore multi-target drugs with reliable efficacy and little side effects.

EFFECT OF BIOACTIVE COMPOUNDS ON BONE DESTRUCTION IN RA
TCM in the treatment of rheumatism has a history of thousands of years, especially the single TCM and its bioactive compounds, which is more popular in recent years, the therapeutic effect of TCM on bone destruction has gradually become a new research hotspot (Shen et al., 2019). A large number of experimental studies have been carried out, which directly or indirectly verified the role of TCM in inhibiting bone destruction in RA from different perspectives. These studies have shown that bioactive compounds extracted from TCM could downregulate bone destruction promoting factors and up-regulate bone protective factors (Cai X. et al., 2018). Due to its diversified action ways and targets, TCM may have potential advantage in restraining RA bone destruction. Therefore, in this review, we elaborated the potential mechanisms of bioactive compounds extracted from TCM in the treatment of bone destruction in RA and divide them into alkaloids, saponins, flavonoids, and so on.
SIN is a kind of bioactive compound extracted from the medicinal rhizome of Sinomenium acutum (Thunb.) Rehder & E.H. Wilson, which has been used in the treatment of various diseases for hundreds of years. SIN is one of the strongest histamine-releasing agents, and has been proved to have antiinflammatory, immunosuppressive, analgesic, antihypertensive, and anti-arrhythmic effects (Sun et al., 2010). In China and Japan, several SIN preparations have been used for RA in clinical practice, such as Zhengqing Fengtongning sustained-release tablets, SIN hydrochloride injection (Liu et al., 2016). The pharmacological basis of SIN in the treatment of RA lies in its anti-inflammatory, analgesic and immunosuppressive effects. Wei-Wei Liu et al. systematically evaluated the efficacy and safety of SIN in treating RA by searching the Pubmed, Cochrane Library, and other databases electronically, and including sixteen randomized controlled trials (RCTs) involving 1,500 subjects; the results of this meta-analysis indicated that SIN had better clinical efficacy and relatively fewer adverse events in the treatment of RA when compared to MTX (Liu et al., 2016). Initially, the effect of SIN on RA is the inhibition of synovitis. Related studies have confirmed that SIN exerted an effect on anti-inflammatory and immunomodulatory activities in the treatment of synovitis in RA by inhibiting proinflammatory cytokines, inhibiting synovial cells proliferation and T cell activation, and regulating monocyte/macrophage subsets (Zhao et al., 2007;Zhang et al., 2015;Liu et al., 2016). In addition, the preponderance of SIN in the treatment of bone destruction in RA are gradually emerging with the deepening of basic research. On one hand, SIN can indirectly inhibit bone destruction in RA by inhibiting the secretion of proinflammatory cytokines. on the other hand, it can directly inhibit osteoclast-mediated bone resorption (Bao et al., 2017;Liu et al., 2018). NFATc1 is one of the important transcription factors that induce osteoclast differentiation, and it can induce the formation of osteoclast specific genes such as TRAP, CTR and CTSK (Li H. et al., 2018). Recent studies have shown that NFATc1 is mainly activated through NF-kB and Ca 2+ signaling pathways (Bendickova et al., 2017). Long-gang He et al. found that SIN inhibited the expression and transcriptional activity of NFATc1 mRNA during the differentiation of human peripheral blood mononuclear cells into osteoclasts induced by lipopolysaccharide (LPS), and the main mechanism was to inhibit the activation of NF-kB and reduce the level of Ca 2+ in cells (He et al., 2016). In addition, SIN also reduced the breast cancer cells induced bone destruction by inhibiting the protein activity of NFATc1 (Zhang et al., 2019b). The OPG/RANKL ratio plays a decisive role in osteoclast differentiation. SIN regulated OPG/RANKL ratio induced by PGE2 and reduced the amount of TRAP-positive multinucleated osteoclasts which differentiated from RAW264.7 cells . Another study showed that SIN obviously reduced the activation of caspase-3 and the phosphorylation of p38 (p-p38), and JNK (p-JNK) in RANKL-stimulated RAW264.7 cells, but has no effect on ERK1/2 posphorylation (He et al., 2014;Li X. et al., 2013). Xiaojuan Li et al. confirmed that SIN prevented the reduction of tissue mineral density (TMD), bone mineral density (BMD), trabecular number (Tb. N), trabecular thickness (Tb. Th), as well as the activity of TRACP5b and ALP in RA rat model induced by M. tuberculosis H37Ra (Mt) . The inhibitory effect of SIN on bone resorption was also confirmed in collagen-induced arthritis (CIA) rats that SIN reduced the level of MMP-3 and MMP-13 in serum and RANKL protein expression in the synovium (Sun et al., 2014). Obviously, SIN has a good prospect and application potential in the field of clinical treatment of bone destruction in RA. However, current researches of SIN were mainly focused on its inhibitory effect on bone resorption, its effect on bone formation in RA is still unknown and needs further research. Meanwhile, the adverse effects caused by SIN through histamine release, such as allergic reactions and gastrointestinal reactions, have severely impeded the further clinical application of SIN. For people with allergic constitution, SIN should be taken in small doses and the use of SIN should be cautious; and it is suggested to avoid taking highfat and high-protein diets during administration. For digestive tract reactions, appropriate preparation forms should be selected to alter the irritation and instability of SIN. Hence, further studies are urgently needed to explore the possibilities of decreasing the clinical adverse effects of SIN.
Besides SIN, other alkaloids also have the effect on bone destruction in RA. As a potential ligand of aryl hydrocarbon receptor (AhR), TET markedly inhibited the differentiation of RAW264.7 cells and bone marrow-derived macrophages (BMMs) into osteoclasts through AhR/c-Src/c-Cbl signal pathway. Moreover, bone mineral density (BMD) and trabecular bone (Tb) of bone parameters increased in CIA rats significantly after continuous administration of TET (Yuan et al., 2016;Jia et al., 2018;Jia Y. et al., 2019). NOR is the main isoquinoline alkaloid that inhibited the differentiation of osteoclasts via MAPK/NF-kB/c-fos/NFATc1, HIF, and p38/ ERK/AKT/AP-1 signal pathway, and it also significantly reduced the number of TRAP-positive multinucleated osteoclasts in the joints of CIA rats as well as the levels of RANKL, IL-6, PGE2, and MMP-13 in serum of AIA rats independently of its anti-inflammatory effect, but the results also showed that NOR could not reduce the levels of OPG and MMP-1 (Luo et al., 2010;Wei et al., 2013a;Wei et al., 2013b;Wei et al., 2015). All these experimental evidences have been summarized in Table 1.
Berberine, magnoflorine, ligustrazine, and other alkaloids have been confirmed to inhibit the bone resorption or promote the bone formation in vitro, but whether they have any effect on bone destruction in RA is still unknown and needs to be verified in vivo Wang et al., 2017;Cai Z. et al., 2018;Dinesh and Rasool, 2018). Collectively, most of the alkaloids play a role in relieving bone destruction by inhibiting the formation, differentiation and maturation of osteoclasts, and their biological activities may be related to their special structure which need to be explored by more related researches. The major challenges associated with alkaloid researches are the poor water solubility and low bioavailability which will limit their oral administration. Low bioavailability may be resolved by using semisynthetic and biochemical transformation approach. Most of the alkaloids have different biological characteristics, and biosynthesis of these agents is also varied. Therefore, it is indeed a daunting task to indicate the common mechanisms of action for alkaloids, because compounds exhibit differential cellular and molecular mechanisms even within a particular structural class. Hence, more studies in vitro and in vivo are needed to verity the effects of alkaloids agents on bone destruction in RA.

Saponins
Saponins are linked by hydrophobic sapogenins and hydrophilic glycosyl groups through glycosides which the main components are triterpenes or spiral steranes. They have the activities of antiinflammatory and improving body immunity (Zhao Y. et al., 2018). Saponins' bone protection is also very prominent, triterpenoid saponins such as asperosaponin VI (ASA VI), ginsenoside Rg1, notoginsenoside R1, glycyrrhizin, and steroidal saponins such as dioscin, all of them are boneprotective saponins. The repair effect of ASA VI, ginsenoside Rg1 on bone destruction in RA has been confirmed.
ASA VI is the main bioactive compound of Dipsacus japonicus Miq., which has a wide range of pharmacological effects. Its pharmacological activities in neuroprotection, prevention of osteoporosis, anti-apoptosis, analgesia, etc. that have attracted the attention of the majority of scholars, and has high research and development value (Ke et al., 2016). Liu et al. demonstrated ASA VI inhibited osteoclast differentiation to protect bone tissue, it reduced the levels of TNF-a and IL-1b in serum of CIA mice, and significantly reduced the expression of TRAP, CTSK, MMP-9 and b3-integrin involved in bone resorption, in addition, the formation of F-actin ring induced by RANKL in BMMs significantly inhibited, as well as the phosphorylation levels of AKT, JNK, and p38 . ASA VI not only inhibited osteoclast differentiation, but also promoted osteoblast differentiation. ASA VI induced osteoblast maturation and differentiation, and then increase bone formation in MC3T3-E1 and primary osteoblastic cells via increasing BMP-2 synthesis, and activating p38 and ERK1/2 (Niu et al., 2011). Ding et al. demonstrated ASA VI enhanced the ALP activity of adipose-derived stem cells (ADSCs), promoted matrix mineralization, and up-regulated the phosphorylation of bone-related proteins OCN, Runx2, and Smad2/3, which promoted the osteogenic differentiation of ADSCs (Ding et al., 2019). Although the pharmacological action of ASA VI has a wide application prospect, its development and popularization are greatly limited by its poor bioavailability. It is suggested that it can be further improved through preparation technologies such as nano-drug delivery system, sustained and controlled release drug delivery system and so on.
Ginsenoside Rg1 effectively controlled the bone damage in CIA mice, which was mainly manifested by significant decrease in the number of osteoclasts in the interphalangeal joint and ankle joint, and the expression of TRAP, CTSK, MMP and calcitonin receptor (CTR) induced by RANKL was inhibited (Gu et al., 2014). This bone-protective effect was also effective in AIA rats, after intraperitoneal injection of ginsenoside Rg1 for 14 days, the levels of TNF-a and IL-6 in the blood of AIA rats were significantly decreased. In addition, Rg1 increased the expression of peroxisome proliferators-activated receptors-gamma (PPAR-g) protein and inhibited NF-kB nuclear translocation in RAW264.7 cells stimulated by lipopolysaccharide (LPS) . All these experimental evidences have been summarized in Table 2.
In vitro studies, it has been proven that notoginsenoside R1, glycyrrhizin, dioscin, and other saponins can inhibit the osteoclasts' differentiation or promote the osteoblasts' differentiation, but their effect on bone destruction in RA requires the verification of relevant animal experiments Qu et al., 2014;Wang et al., 2015). Based on the above findings, we can find that most of the saponins (mainly triterpenoid saponins) play a role in bone resorption or bone formation. However, it is not known whether triterpenoid saponins and steroidal saponins have different pharmacological effects on bone-protection, whether the bone protection of steroidal saponins is affected by the structural changes of liver microsomes. Therefore, a large number of related experiments are still needed. Similarly, because of the structural diversity and complexity of saponins, the acquisition of many saponins is still a difficult task, which greatly limits the further exploration of saponins' pharmacological activity and mechanism. In addition, the bioavailability of most saponins is low after oral administration, which also brings difficulties to the research of new drugs based on active natural saponins.

Flavonoids
Flavonoids generally refer to a series of bioactive compounds formed by the connection of two benzene rings with phenolic hydroxyl groups (A and B rings) through the central three carbon atoms. They have the effects of anti-inflammation, antioxidation, scavenging free radicals and so on (Wen et al., 2017). The bioactive compounds of flavonoids for protecting effect on bone by acting on osteoclasts or osteoblasts include kaempferol (KP), quercetin, icariin, poncirin, baicalin, silibinin, etc. The repair effect of KP, quercetin, icariin on bone destruction in RA has been confirmed. KP is a natural flavonol-type flavonoid, which is present in the rhizomes of the ginger plant Kaempferia galanga L. According to literature reports, previous studies have shown that KP has many pharmacological effects, such as anticancer, antiinfl ammatory, antioxidant, antibacterial, antiviral, immunosuppressive, etc (Calderoń-Montaño et al., 2011;. KP is the basis of the quality control standard of Duanteng Yimutang preparation for clinical treatment of RA, the mechanism and molecular target of KP in the treatment of RA can provide more theoretical support and basis for its clinical application. The effect of KP on synovitis is shown that it inhibited proliferation, induced apoptosis, and ameliorated inflammation in fibroblast-like synoviocytes by suppressing the NF-kB and AKT/mTOR pathways or targeting on the fibroblast growth factor receptor 3 (FGFR3)-ribosomal S6 kinase 2 (RSK2) signaling axis . In addition to its inhibitory effect on synovitis, KP also showed bone-protecting effect in the treatment of RA. KP's bone-protective function in RA is to inhibit pro-inflammatory cytokines indirectly, it also can directly act on osteoclast-mediated bone resorption or osteoblastmediated bone formation. Alice Wattel et al. explored the effect of KP on bone resorption for the first time, they found KP directly induced apoptosis of mature osteoclasts in the highly purified rabbit osteoclasts, and its estrogenic effect could be involved in the inhibition of bone resorption (Wattel et al., 2003). KP inhibited RANKL-induced expression of c-fos, c-RANK and CTR in RAW264.7 cells, however, TNF-astimulated intracellular ROS production was unaltered by KP (Pang et al., 2006). KP inhibited IL-1b-stimulated, RANKLmediated the expression of NFATc1, phosphorylation of ERK 1/2, p38 and JNK MAP kinases in bone marrow cells . Autophagy has pivotal roles in maintaining bone metabolic balance. Sequestosome 1 (p62/SQSTM1) is an important bridge protein that becomes incorporated into autophagosomes in RANKL-induced autophagy and osteoclastogenesis (Rea et al., 2013). Kim et al. found KP inhibited autophagy and promoted apoptotic cell death in RAW 264.7 cells by the degradation of p62/SQSTM1. KP's main manifestation of inhibiting osteoclastogenesis was to abrogate the formation of TRAP-positive multinucleated cells induced by RANKL in this in vitro experiment (Kim C. J. et al., 2018). There are studies that showed the direct effects of KP on osteoblastic cells or osteoblastic precursor cells by different mechanisms. KP's estrogenic effect acted on osteoblast differentiation, KP induced the activity of osteoblast differentiation biomarkers including ALP, OCN, osterix, Runx2 by estrogen receptor activation in rat primary osteoblasts (Guo et al., 2012). Interestingly, KP-mediated autophagy promotes osteoblast differentiation and bone mineralization. Kim et al. found KP increased the expression of the autophagy-related factors beclin-1, p62/SQSTM1, and the expression of osteoblast-related factors Runx2, osterix, BMP-2, and collagen I also decreased with dose dependent under the concentration of 10 mM in MC3T3-E1 cells (Kim et al., 2016). With further insights into the mechanism of bone-protective action of KP, Yang Wang et al. found KP's regulation of Wnt/b-catenin pathway was to up-regulate the microRNA-101 in MC3T3-E1 cells . The effect of KP on bone destruction in RA has also been confirmed in vivo. After intragastric administration of KP, the effect of synovitis on the invasion of surrounding bone and the level of MMP were suppressed in CIA model (Pan et al., 2018). Furthermore, KP inhibited the progressive structural destruction of RA joints by blocking the bFGF/FGFR3/RSK2 signaling axis in CIA model, the mainly manifest was shown as decreased the levels of osteoclast specific genes TRAP, CTR, CTSK, c-jun, and p50 . Though KP's poor bioavailability represents a significant obstacle, the use of KP-based nanoparticles has brought more hope on chemoprevention strategies. While KP shows potential for improving bone destruction by the alterations of osteoclast or osteoblast related protein genes or RNAs, but most of the research conducted on KP resistance to bone destruction potency was in vitro, making it difficult to draw a final conclusion on its usefulness, in vivo studies and clinical trials are scarce so far, thus stressing the need for more in-depth experiments.
Quercetin and icariin are two other flavonoids with the effect of treating bone destruction in RA. Quercetin not only inhibited the expression of osteoclast-specific genes TRAP, CTSK, NFATc1 in vitro, and the plasma level of MMP-3, MMP-9 in CIA mice, but also up-regulated the mRNA and protein expression of osteoblast-specific genes Osx, Runx2, ALP and OCN Haleagrahara et al., 2018;Kim H. R. et al., 2019). Icariin blocked osteoclast generation by inhibiting the expression of TRAF6 in the early stage of osteoclast formation and the activation of ERK1/2 and NF-kB. In addition, the decrease of F-actin ring formation revealed that bone resorption capacity of mature osteoclasts was inhibited by Icariin. Moreover, Icariin's inhibitory effect on bone resorption in RA has also been confirmed in CIA model (Chi et al., 2014;Xu et al., 2019). All these experimental evidences have been summarized in Table 3.
Poncirin, baicalin, silibinin, and other flavonoids have been shown significant effects on osteoclasts or osteoblasts (Kim et al., 2009;Lu et al., 2017;Chun et al., 2020). But whether they can repair bone destruction in RA is not verified which need a large number of relevant animal experiments. Actually, most of the flavonoids play a role in bone resorption or bone formation by different signal transduction mechanisms. Autophagy may be involved in, but still need conduct appropriate animal experiments. The difference between protective autophagy and inhibitory autophagy induced by flavonoids may be related to the type, mode and dose of flavonoids, as well as the type and the state of the cell lines. Moreover, most flavonoids have low cytotoxicity to normal cells at normal dose, and are safer than traditional cytotoxic drugs, so they have strong potential for clinical application.
The repair effect of TP, celastrol, artesunate on bone destruction in RA has been confirmed.
TP (a dierpene triepoxide in chemical structure), extracted from Tripterygium wilfordii Hook.f., is a kind of natural product with various biological activities. It attracted worldwide attention in the 1960s because of its pharmacological effects in a variety of diseases such as RA, no small cell lung cancer, and refractory nephrotic syndrome (Yuan et al., 2019). TP has been considered as a promising anti-RA drug which has definite effects including immunosuppression, anti-inflammatory reaction, inducing apoptosis, inhibiting angiogenesis . Tripterygium wilfordii tablets, Tripterygium wilfordii glycosides tablets, and Tripterygium hypoglaucum hutch tablets which take triptolide as the quality control standard are available in clinic (Law et al., 2011). The pharmacological effect of TP on synovitis is the focus of researchers to explore the mechanism of triptolide in the treatment of RA at the very start. TP treated synovitis in RA by regulating immune-related cells (such as T cells, macrophages, dendritic cells), immune-related inflammatory mediators and immune-related angiogenesis (Chan et al., 1999;Zhu et al., 2005;Kong et al., 2013). With the research developed, researchers found that delaying or even blocking bone destruction is another primary mechanism of TP in the treatment of RA. Zhu et al. systematically evaluated the effect of Tripterygium wilfordii glycosides tablets in the treatment of RA by searching the Pubmed, Web of Science, Cochrane Library and other databases, three RCTs were employed which involved a total of 223 subjects, and the results indicated that Tripterygium wilfordii glycosides tablets had a good effect on regulating the modified Sharp score (m TSS), tender join joint erosions (JE) and joint space narrowing (JSN), and the effect is better than the positive drugs MTX and sulfasalazine, which reflected the advantages of TP in the treatment of bone destruction in RA (Zhu G. Z. et al., 2019). As a typical anti-inflammatory drug, TP indirectly treated bone destruction in RA by inhibiting the levels of pro-inflammatory cytokines such as TNF-a and IL-1b and promoting the secretion of IL-10 and TGF-b1 derived from T cells (Xu et al., 2016). RANK-RANKL signaling activates a variety of downstream signaling pathways required for osteoclast development. TP suppressed RANKL-induced NF-kB activation in osteoclast precursor cells by inhibiting IkBa kinase activation, IkBa phosphorylation, and IkBa degradation effectively, and osteoclast formation induced by tumor cells was inhibited (Park, 2014). Spleen cells are also one of the main sources of osteoclast precursors, low-dose TP promoted the apoptosis of osteoclast precursors by inhibiting the overexpression of cellular inhibitor of apoptosis protein 2 (cIAP2) in fresh spleen cells induced by M-CSF . AKT-MDM2-induced cell death might contribute to the osteoclastogenesis suppression. Cui et al. found TP suppressed NFATc1 overexpression and AKT phosphorylation when PI3K-AKT-NFATc1 pathway was activated induced by RANKL in BMMCs or RAW264.7 cells (Cui et al., 2020). The therapeutic effect of TP on bone destruction in RA has been confirmed in vivo, TP improved bone destruction of TNF-Tg mice by decreasing the levels of pro-inflammatory cytokines, promoting the apoptosis of osteoclast precursors and inhibiting the generation of osteoclast . The result of Micro CT showed that TP significantly increased joint bone density, bone volume fraction and trabecular thickness of CIA mice, reduced trabecular separation of inflammatory joints through inhibiting the expression of RANKL and increasing the expression of OPG . Although TP has already been proved to have potential advantages in the treatment of bone destruction in RA in vitro and in vivo, its precise molecular targets that responsible for the potent biological activity have not been fully identified yet. At the same time, the side effects of TP are to block its clinical application to a great extent, development of efficient TP-targeted delivery system is an available strategy to realize targeted delivery of TP with reduced toxicity. Celastrol and artesunate are two other terpenoids with the effect of treating bone destruction in RA. Celastrol played an inhibitory effect against the formation and function of osteoclasts by regulating the ratio of RANKL/OPG and the expression of transcription factors in osteoclasts induced by RANKL, the main mechanisms involved the phosphorylation of NF-kB and MAPK (Nanjundaiah et al., 2012;Gan et al., 2015;Cascao et al., 2017). Artesunate down-regulated the expression of osteoclast-specific genes TRAP, CTSK, c-fos, and NFATc, as well as the expression of MMP-9 protein in CIA model hind paw by inhibiting the ERK and JNK phosphorylation Wei et al., 2018). All these experimental evidences have been summarized in Table 4.
Parthenolide, AP and other terpenoids exerting an effect on osteoclasts or osteoblasts has been found in vitro (Kim et al., 2014;Qu et al., 2014;Zhang et al., 2014;Li et al., 2016). But whether they have any effect on bone destruction in RA is unknown, it is critical to verified terpenoids' pharmacological action of bone protection in vivo. Terpenoids are expected to become the main drugs for the treatment of bone destruction in RA with its significant pharmacological effects, low toxicity and side effects, but the efforts to further improve terpenoids' efficacy are limited because of the unclear structure-activity relationship. Therefore, it is necessary to explore new technical measures to definite the structure-activity relationship.

Phenols
Phenols is a kind of bioactive compound, and its hydroxyl group is directly connected to benzene ring or other aromatic ring. Phenols has strong effects of anti-oxidation, anti-atherosclerosis, anti-infection, anti-tumor, and anti-osteoporosis (Zenkov et al., 2016). The bioactive compounds of terpenoids for protecting effect on bone by acting on osteoclasts or osteoblasts including resveratrol (RES), ferulic acid (FA), curcumin, gastrodin, paeonol, etc. The repair effect of RES, FA on bone destruction in RA has been confirmed.
RES, extracted from Reynoutria japonica Houtt., is a naturally occurring polyphenolic compound containing stilbene structure. It has reported that RES has positive effects on health and increase life span (Baur and Sinclair, 2006). RES mainly functioned on the centrum restraint, heart sturdiness, inflammation diminishing, and anti-cancer (Ko et al., 2017;Wahab et al., 2017). At present, the role of RES in the treatment of RA is particularly remarkable because of its unique anti-infl ammatory and immunosuppressive pharmacological effects. RES treated RA by enhancing the apoptosis of fibroblast-like synoviocytes, inhibiting angiogenesis, etc, the mechanism of its inhibition of synovitis included the regulation of NF-kB, MAPK-p38, JAK/STAT, PI3K/AKT, etc signaling pathways Yang et al., 2018;Zhang et al., 2019a). As a natural phytoestrogen, RES acts as an estrogen receptor agonist which obviously promotes bone growth under normal bone growth environment and protects bone under weightlessness and diseases (Baur and Sinclair, 2006). The dosage forms of RES used for RCT to investigate the effects of RES on bone in type 2 diabetic patients or metabolic syndrome (MetS) include RES tablets and RES capsules, these clinical trials further confirmed the protective effect of RES on bone (Ornstrup et al., 2014;Bo et al., 2018). RES is reported to impact bone destruction by increasing osteoblast differentiation and function in vitro. RES at non-toxic concentrations dose-dependently inhibited RANKLinduced osteoclast differentiation and induced osteoclast apoptosis by inhibition of ROS generation (He et al., 2010). RES improved the oxidative stress state of RAW264.7 cells, thus inhibited the mRNA expression of osteoclast specific enzyme MMP-9, TRAP, CTSK, this was the first time to confirm that RES promoted resistance to oxidative damage and restrained osteoclastogenesis by inhibiting the PI3K/AKT signaling pathway at the molecular level . The role of RES in promoting osteoblast differentiation may be more prominent. RES suppressed OCN synthesis in osteoblasts induced by stimulating factors (triiodothyronine or BMP-4) via the activation of SIRT1 or the amplification of p38 MAP kinase activity (Kuroyanagi et al., 2015;Fujita et al., 2017). Although RES indirectly promoted osteoblast differentiation by inhibiting inflammation, RES promoted the increase of ALP and OPG in BMSCs induced by LPS, but did not decrease the levels of IL-6 and IL-8, the result indicated RES's effect on osteoblasts could be independent of inflammation. Meanwhile, the Wnt/bcatenin and ERK/MAPK signaling pathways also participated in the mechanism of RES's bone-protection (Ornstrup et al., 2016;Zhao X. E. et al., 2018). Silent information regulator 2 homologue 1 (SIRT1) is a positive regulator of the master osteoblast transcription factor, RES reduced the decrease of OCN, OPN, and RUNX2 expression in MC3T3-E1 cells induced by LPS, and the main possible mechanism was to regulate mitochondrial function of osteoblasts by increasing the expression of SIRT1 . Yaqiong Yu et al. found a new mechanism of RES promoting osteoblast differentiation under the same result, the activation of AMP-activated protein kinase (AMPK) phosphorylation and inhibitor of suppressor of cytokine signaling 1 (SOCS1) were important signal events that RES inhibited LPS-induced MMP-2 production in MC3T3-E1 cells . The potential protective effects of RES on bone destruction in RA has been confirmed in vivo, RES significantly improved the narrowing of joint space, and the expression level of MMP1 and MMP13 in the synovial tissue was significantly reduced in CIA rats (Hao et al., 2017). Similarly, the expressions of MAPK, Src kinase, STAT3, and Wnt5a in the CIA model joint tissue also participated in the repairing effect of RES on bone destruction in RA (Oz et al., 2019). More and more experimental studies have emphasized the immunomodulatory and osteoprotective effects of RES in vivo and in vitro. Although these studies have produced exciting results, we still faced with some problems such as poor water solubility and low bioavailability. Therefore, various strategies are being implemented, including the development of RES-related preparations (nanoparticles, liposomes, micelles and phospholipid complexes, etc.) to improve their bioavailability. In addition, several other methods have been used to improve its bioavailability, including changing the route of administration of resveratrol and blocking the metabolic pathway through treatment with other drugs. In fact, since RES has multiple intracellular targets, additional data are needed to determine the results of interactions or synergies between other polyphenols. FA has the functions of anti-inflammatory, anti-oxidation, inhibiting platelet aggregation, improving microcirculation, and so on (Zheng et al., 2019;Perez-Ternero et al., 2017). Zhu et al. found FA significantly alleviated joint swelling and reversed the increase of C-reactive protein (CRP) and rheumatoid factor (RF) in CFA rats, its protective mechanism on joints is mainly to reduce the secretion of TNF-a and increase the secretion of TGF-b by inhibiting JAK/STAT pathway (Zhu et al., 2020b). Sagar et al. found that FA inhibited the expression of DC-STAMP which is necessary for the differentiation and maturation of osteoclasts, as well as inhibited RANKL-induced upregulation of MMP-9 and CTSK. In addition, it induced mature osteoclast apoptosis through the caspase-3 pathway (Sagar et al., 2016). Scanning electron microscopy and TRAP staining analysis showed that FA significantly inhibited the osteoclast differentiation induced by RANKL, it inhibited the formation of mature osteoclasts by inhibiting the expression of NFATc1 and c-fos, it further inhibited the bone resorption activity of mature osteoclasts by inhibiting the expression of TRAP, MMP-9, and CTSK (Doss et al., 2018). All these experimental evidences have been summarized in Table 5.
In vitro studies, it has been found that curcumin, gastrodin, paeonol and other phenols can also inhibit bone resorption or promote bone formation (Zhou F. et al., 2017;Li et al., 2019;. However, we need more experiments in vivo to explore their effects on bone destruction in RA. Phenols has good antioxidant activity because of the high reactivity of hydroxyl substitution and the ability to engulf free radicals. It is known that oxidative stress can improve the activity of osteoclasts, whether phenols' antioxidant properties are closely related to its pharmacological effects on osteoclasts or osteoblasts needs to be further studied.

CONCLUSION AND FURTHER PERSPECTIVES
Bone destruction in RA is difficult to cure, and the disability rate is high, which is a serious threat to human health. Therefore, it is particularly important to find more effective and reliable treatment methods and means. TCM in the treatment of RA has a long history, the research of TCM in the treatment of bone destruction in RA has made rapid progress, which shows that TCM has strong advantages and characteristics in the treatment of bone destruction in RA. These bioactive compounds extracted from TCM display anti-bone destructive activity in vitro and in vivo, and they have shown very good results from different aspects. The potential of bioactive compounds extracted from TCM to provide or inspire the development of anti-bone destruction bioactive drugs is, therefore, really quite evident. However, the biological tests about these compounds and test results are different, mainly due to the different extraction protocols, compounds purity and intervention projects (including doses, animal, or cell models, test methods, and so on). Even compounds with the same purity in the study may have different test results and will make people doubt the authenticity of these tests. Therefore, it has become necessary to use some advanced and interdisciplinary technology and methodology unify extraction protocols and purity  (Doss et al., 2018) identification standard. Furthermore, the studies on compounds are only in the early stage, most of them are focused on in vitro experiments. Hence, additional investigation into pharmacokinetics with animal models and clinical studies are necessary. In addition, proper dosage needs to be considered to prevent the potential toxicity when developing these compounds into clinically viable drugs. Similar compounds can treat bone destruction of RA through different signal transduction mechanisms. Whether these mechanisms are interrelated, and whether compounds with the same or similar structures have similar pharmacological effects on osteoclasts or osteoblasts remain to be further verified. Combinations of different compounds that regulate bone destruction in RA through different mechanisms may have synergistic or cumulative effects. This also needs to be further verified. It is hoped that this review can highlight the importance of bioactive compounds extracted from TCM in the treatment of bone destruction in RA and provide a new direction for future researchers. In the future, we need advanced technology to separate more bioactive compounds from TCM for the treatment of bone destruction in RA, and further explore the exact molecular mechanism and therapeutic targets of the bioactive compounds, which will be helpful for the treatment of bone destruction in the early stage, preventing disability and enhancing the quality of patients' life.

AUTHOR CONTRIBUTIONS
YS wrote the manuscript. HS, XW, and HZ contributed to the literature research for the manuscript. CL revised the manuscript. AL and XH revised and approved the manuscript. All authors contributed to the article and approved the submitted version.