Recent advance in treatment of osteoarthritis by bioactive components from herbal medicine

Osteoarthritis (OA) is a common chronic articular degenerative disease, and characterized by articular cartilage degradation, synovial inflammation/immunity, and subchondral bone lesion, etc. The disease affects 2–6% of the population around the world, and its prevalence rises with age and exceeds 40% in people over 70. Recently, increasing interest has been devoted to the treatment or prevention of OA by herbal medicines. In this paper, the herbal compounds with anti-OA activities were reviewed, and the cheminformatics tools were used to predict their drug-likeness properties and pharmacokinetic parameters. A total of 43 herbal compounds were analyzed, which mainly target the damaged joints (e.g. cartilage, subchondral bone, and synovium, etc.) and circulatory system to improve the pathogenesis of OA. Through cheminformatics analysis, over half of these compounds have good drug-likeness properties, and the pharmacokinetic behavior of these components still needs to be further optimized, which is conducive to the enhancement in their drug-likeness properties. Most of the compounds can be an alternative and valuable source for anti-OA drug discovery, which may be worthy of further investigation and development.


Background
Osteoarthritis (OA) is a common chronic articular degenerative disease, and characterized by articular cartilage degradation, synovial inflammation/immunity, and subchondral bone lesion, etc. [1,2] The disease affects 2-6% of the population around the world, and its prevalence rises with age and exceeds 40% in people over 70 [1]. Treatment for OA can be divided into non-surgical (e.g. acetaminophen, nonsteroidal anti-inflammatory drugs, and hyaluronic acid, etc.) and surgical (e.g. osteotomy, unicompartmental knee arthroplasty, and total knee arthroplasty) management [1]. However, these current treatments are also accompanied by a series of complications, such as pain, infection, blood problem, and so on [1]. Thus, it can be seen that exploring more safe and effective treatments for OA still need to be carried out on an ongoing basis.
The smooth progress of drug research and development needs the support of the corresponding pathological models. The commonly used methods of mimicking OA include surgical (e.g. Hulth technique, joint immobilization, and destabilization of the medial meniscus, etc.) and non-surgical (e.g. monosodium iodoacetate, papain, and collagenase, etc.) induction [3][4][5][6][7][8]. The model animals (e.g. mouse, rat, and rabbit, etc.) and human biological samples (e.g. cartilage, peripheral blood mononuclear cell, and fibroblast-like synoviocytes, etc.) are selected as the research object to evaluate the anti-OA mechanism of the drug.
In recent years, increasing interest has been devoted to the treatment or prevention of OA by herbal medicines. OA is a kind of "deficiency syndrome" in traditional Chinese medicine theory [9]. A variety of traditional Chinese medicines with tonifying deficiency effects show the potentials to treat OA [10,11]. Additionally, herbal compounds with cartilage-protective, anti-inflammatory or antioxidant effects have also been widely used in the treatment of OA [12][13][14]. Therefore, the herbal compounds with anti-OA activities were reviewed in this paper, and the cheminformatics tools were used to predict their drug-likeness properties and pharmacokinetic parameters, so as to provide the references for their follow-up researches and developments.

The anti-OA activities of bioactive components from herbal medicines
Information on the treatment of OA by bioactive components from herbal medicines was collected by using Google Scholar (http://schol ar.googl e.com) and Pub-Med (https ://www.ncbi.nlm.nih.gov/pubmed). From herbal medicines, 43 bioactive components with anti-OA activities have been isolated, including 11 terpenoids, 10 flavonoids, 7 alkaloids, 6 phenols, 3 quinones, 2 coumarins, 2 lignans, 1 steroids, and 1 furans (Additional file 1: Figure S1). The networks of OA pathogenesis and compound targets were constructed by Cytoscape software (version 3.8.0). OA is mainly characterized by joint degeneration, meanwhile accompanied by the changes of the related indicators in circulatory system (Fig. 1). Multiple pathological processes are involved in the pathogenesis of OA, such as inflammation, apoptosis, and oxidative stress, etc. (Figure 1). These bioactive components (such as resveratrol, curcumin, and isofraxidin, etc.) mainly target the damaged joints (e.g. cartilage, subchondral bone, and synovium, etc.) and circulatory system to improve the pathogenesis of OA, which mainly exert anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects through interleukin (IL), nuclear factor-κB (NF-κB), and matrix metalloproteinase (MMP) pathways (Figs. 2 and 3). The effective doses of these compounds for the experiment are shown in Table 1.

The effects of bioactive components on cartilage in OA
Cartilage is pivotal to the normal function of synovial joints. Cartilage covers and protects the ends of long Fig. 1 The main pathogenesis and lesion sites of OA. Blue circular node: pathogenesis; red diamond node: cartilage damage; green diamond node: subchondral bone damage; blue diamond node: synovial injury; pink diamond node: circulatory system changes; purple diamond node: muscle weakness and inflammation bones permitting friction-free locomotion and movement at the joints. A dysfunction in the cartilage is one of the important inducing factors and pathological features of OA [14]. Cartilage consists of chondrocytes that generate a large of collagenous extracellular matrix, proteoglycans, and elastin fibers. Histological analysis shows that various components can repair the damage of chondrocytes in OA, including resveratrol [14], curcumin [15], icariin [16], berberine [17], sinomenine [18], tetramethylpyrazine [19], halofuginone [20], quercetin [21], psoralen [22], and magnoflorine [23].

The effects of bioactive components on subchondral bone in OA
Besides cartilage, subchondral bone lesions are the characteristic pathological changes in OA as well [91]. The micro-computed tomography scan shows that halofuginone restores coupled bone remodelling and aberrant angiogenesis in subchondral bone [82,91]. Osteoclast is a type of bone cell breaking down bone tissue, and collagen degradation mediated by which is also involved in the pathophysiology of OA [57]. Icariin [92] and sinomenine [93] suppress osteoclastogenesis through osteoprotegerin-NF-κB system. Halofuginone suppresses Th17-induced osteoclastogenesis via inhibition of TGF-β signaling [82]. Artesunate interrupts anterior cruciate ligament transection-associated osteoclastogenesis [57]. In addition to osteoclasts, osteoblasts are also the major cellular component of bone, which synthesize dense and crosslinked collagen and reshape bone tissue. Magnoflorine [23] and compound K [37] stimulate osteoblast proliferation, differentiation, and mineralization. Resveratrol may play the roles on alkaline phosphatase activity, osteocalcin release, and mineralization in osteoblasts via promoting the Wnt/β-catenin signaling pathway [94]. Histological analysis indicates that cryptotanshinone [29], isofraxidin [34], and resveratrol [77] may reduce subchondral bone plate thickness.

The effects of bioactive components on synovium in OA
Synovium supplies nutrients to cartilage and protects the joint structures and the adjoining musculoskeletal tissues [95]. OA is a classic degenerative synovial disease. Synovitis affects both symptoms and progression of OA [95]. Curcumin [96,97], icariin [95], psoralen [22], berberine [17], quercetin [98], geniposide [31], sinomenine [99], and artesunate [57,100] produce anti-inflammatory activity in synoviocytes/synovia by regulating the levels of various inflammatory factors, such as MMPs, ILs, and tumor necrosis factor (TNF)-α, etc. Synovial proliferation is induced by inflammation in OA [101]. The antiproliferative effects of curcumin [97] and icariin [95] may reverse this process. Likewise, angiogenesis and inflammation are closely associated in OA [57]. Sinomenine [18] and artesunate [57] may prevent the expression of angiogenic factors (e.g. VEGF, NGF, and angiopoietin-1, etc.). Oxidative stress and inflammation promote each other in joints [98]. Quercetin [98] and geniposide [31] may inhibit oxidative stress in synovial region. Glucose-regulated protein-78 aggregates in the endoplasmic reticulum, which is widely used as a marker for endoplasmic reticulum stress. Icariin can reduce Glucose-regulated protein-78 expression in synovium of OA [95]. Geniposide [31] and sinomenine [102] can decrease the levels of MMPs and cartilage oligomeric matrix proteins in synovial fluid, which may help to alleviate the process of cartilage degradation in OA. Insulin-like growth factor-1 accelerates the differentiation of chondrocytes, stimulates the synthesis of cartilage matrix, and inhibits the matrix decomposition, the up-regulation of which by artesunate may facilitate cartilage protection in OA [100].

The effects of bioactive components on circulatory system in OA
Circulatory pathology is closely related with OA [103]. A variety of herbal compounds can reverse some pathological processes in serum of OA model. Quercetin [104], resveratrol [63,105], sinomenine [99], puerarin [53], isofraxidin [34], naringin [106], ginsenoside Rb1 [87], triptolide [107], and icariin [108] can reduce the serum levels of inflammatory cytokines, such as ILs, TNF-α, and hsa-miR-20b, etc. Sinomenine [102], quercetin [98,104], and artesunate [100] may regulate the expressions of cartilage catabolic factors (e.g. MMPs, tissue inhibitors of MMP, and a disintegrin and metalloproteinase with thrombospondin motifs, etc.) in serum. Icariin reduces VEGF and hypoxia-inducible factor-lα levels in the peripheral blood, which may help to inhibit the formation of new blood vessels in the synovial tissue of joints [9]. Resveratrol effectively improves the blood rheology, which facilitates to prevent and delay the degenerative changes in the articular cartilage of OA model [109]. Additionally, quercetin increases serum superoxide dismutase level, which is a major active molecule to scavenge free radical [98].

The effects of bioactive components on muscle in OA
Muscle weakness and inflammation also play a role in OA development and progression [110]. Crocin attenuates OA symptoms through alleviating muscle oxidative stress (targets: nuclear factor (erythroid-derived 2)-like 2, superoxide anion, and glutathione, etc.) and inflammation (pathways: c-Jun N-terminal kinase, NF-κB, and MAPK, etc. signaling pathways) induction [110].

Pharmacokinetic parameters and drug-likeness properties prediction of bioactive components with anti-OA activities
In addition to their therapeutic activities, the pharmacokinetic behaviors of these components are also the key factors affecting their ability to develop drugs. Only the compounds with good drug-likeness properties have the possibility to be further investigated and developed. Thus, in the following section, the cheminformatics tools were applied to predict the pharmacokinetic parameters and drug-likeness properties of these compounds.
The pharmacokinetic parameters of these compounds were calculated by using pkCSM (http://biosi g.unime lb.edu.au/pkcsm /predi ction ) [111]. The compounds depicted as 2D structures in the MDL Molfile format were imported into the website. The water solubility of the compounds can influence their efficacy in vivo. The good aqueous solubility can facilitate the molecules dispersing into biological body fluids, thereby expediting their absorption and distribution processes [112]. Water solubility assessment showed that most of herbal compounds (38/43) were soluble in water (> − 4 log mol/L), while five of 43 molecules were low soluble in water (< − 4 log mol/L, Table 2). The low solubility of curcumin is one of the factors affecting its oral bioavailability. Reportedly, the solubility of curcumin can be significantly improved by addition of an electron-withdrawing group. A chemically modified curcumin, TRB-n0224, also has good therapeutic effects on OA model [113].
The main pathological features of OA are the degenerative lesions of cartilage and synovium in the joint. It is not conducive to the treatment of local lesions of OA if the distribution of drug molecules in the blood is more than that in the lesion tissues. VDss index can be used to predict the distribution of molecules in tissue and plasma. VDss analysis showed that thirty-six of 43 herbal compounds were mainly distributed in the circulatory system (< 0.45 log L/kg, Table 2). This may require some measures to increase their levels in local tissues. Intraarticular injection allows the molecules to accumulate in the joint cavity, thus enhancing their effects on local lesions. Intra-articular delivery of resveratrol [77], tetramethylpyrazine [80], and anemonin [49] may enhance their articular cavity retention for treating OA.
In addition to intra-articular injection, transdermal delivery of joint is also one of the local administration methods. Extra-articular percutaneous approach has advantages over intra-articular injection, such as greater safety, easier use, better patient compliance, and so on. Skin permeability is the necessary requirement for transdermal drug delivery. Skin permeability estimation indicated that almost all of these herbal molecules (42/43) were easy to penetrate into the epidermis (prediction value less than − 2.5, Table 2), especially anemonin, sinomenine, and triptolide.
The low clearance rate of drugs results in the prolongation of their half-life in vivo. This may produce a sustained and stable curative effect on the chronic diseases, such as OA. At the same time, however, attention should also be paid to the cumulative dose of herbal components with low total clearance. These compounds may also cause cumulative toxicity when they are used for longterm therapeutic purposes. Total clearance prediction showed that fifteen of 43 herbal compounds have the low hepatic clearance and renal clearance rates (prediction value less than 0.25, Table 2), especially celastrol, curcumin, and butein.
The drug-likeness properties prediction of these herbal compounds was analyzed by using MolSoft online tools (http://molso ft.com/mprop /) [114]. The input for the analysis was the MDL Molfile format of these compounds. Over half of these molecules (26/43) had the great possibility of becoming the drugs (prediction value between 0 and 2, Table 2), which have the possibility of being further studied and developed. However, of these compounds, nine molecules had poor drug-likeness properties (prediction value between -3 and − 0.5,

Conclusion and future directions
In this review, we have summarized and analyzed 43 herbal compounds with anti-OA activities. The main therapeutic sites of these molecules for the treatment of OA are articular cartilage, subchondral bone, synovial membrane, and circulatory system, etc. Over half of these compounds have good drug-likeness properties (e.g. naringin, icariin, and quercetin, etc.), which may be worthy of further investigation and development. In addition, these compounds are mainly isolated from Araliaceae, Leguminosae, and Polygonaceae plants, etc., which would get more attention in the following researches. Through cheminformatics analysis, the pharmacokinetic behavior of these components still needs to be further optimized, which is conducive to the enhancement in their drug-likeness properties. The water solubility of molecules can be changed by mean of structural modification, so as to enhance their oral absorption process. In the subsequent distribution process, the accumulation of drug molecules in the joint tissues is conducive to the treatment of the main lesion sites of OA. Both intraarticular injection and articular percutaneous administration can increase the levels of drug molecules in the joint, between which the latter one has a stronger application potential in the treatment of OA. Additionally, the retention time of the components with low clearance rate is increased in vivo, which is conducive to the continuous treatment of OA. However, when used for a long time, their doses should be properly adjusted to avoid cumulative toxicity.
At present, the application of herbal compounds in the treatment of OA has made some progress. However, compared to other arthritis (such as rheumatoid arthritis (RA)), the application of herbal compounds in OA is still inadequate. There is some common pathogenesis between OA and RA, such as inflammation, apoptosis, and oxidative stress, etc. [112]. Therefore, the potential of anti-RA drugs in the treatment of OA would be further explored in future researches. In addition, some new research patterns can be used to speed up the exploration of the mechanism and chemical basis of herbs in the treatment of OA, such as biolabelled research pattern [115,116], chinmedomics [117], and systems pharmacology [118], etc.
Additional file 1: Figure S1. Molecular structures of bioactive components isolated from herbal medicines treating OA.  Water solubility: the solubility of the molecule in water at 25 °C; less than − 10: insoluble; between − 10 and − 6: poorly soluble; between − 6 and − 4: moderately soluble; between − 4 and − 2: soluble; between − 2 and 0: very soluble; more than 0: highly soluble Skin permeability: the human skin permeability of compounds in vitro; more than − 2.5: low skin permeability; less than − 2.5: high skin permeability VDss (human): the volume of compounds distributed in tissue; less than − 0.15: low distribution; more than 0.45: high distribution Total clearance: a combination of hepatic clearance and renal clearance; less than 0.25: low total clearance; more than 0.25: high total clearance DL: drug-likeness model score; between 0 and 2: very drug-like molecules; between − 3 and − 0.5: non-drug like molecules