Skip to main content

Small molecules of herbal origin for osteoarthritis treatment: in vitro and in vivo evidence

Abstract

Osteoarthritis (OA) is one of the most common musculoskeletal degenerative diseases and contributes to heavy socioeconomic burden. Current pharmacological and conventional non-pharmacological therapies aim at relieving the symptoms like pain and disability rather than modifying the underlying disease. Surgical treatment and ultimately joint replacement arthroplasty are indicated in advanced stages of OA. Since the underlying mechanisms of OA onset and progression have not been fully elucidated yet, the development of novel therapeutics to prevent, halt, or reverse the disease is laborious. Recently, small molecules of herbal origin have been reported to show potent anti-inflammatory, anti-catabolic, and anabolic effects, implying their potential for treatment of OA. Herein, the molecular mechanisms of these small molecules, their effect on physiological or pathological signaling pathways, the advancement of the extraction methods, and their potential clinical translation based on in vitro and in vivo evidence are comprehensively reviewed.

Background

Globally, osteoarthritis (OA) is one of the most commonly occurring disorders of articular joints [1,2,3], which typically affects the knees, spine, hands, hips, and feet [4]. The incidence and prevalence reported in epidemiological studies fluctuate widely, as the data may be based on different diagnostic criteria (clinical, radiographic, or pathological OA), various joint locations, and diverse patient populations [5]. The reported prevalence of OA thus ranges from 12.3 to 21.6% [6, 7]. Women are at a higher risk for developing OA as compared to men [2, 7]. The risk further escalates with age, with OA usually occurring in the fourth or fifth decade of life [8, 9]. Furthermore, OA prevalence varies widely in different regions (e.g., developing or developed countries, rural or urban areas) [10,11,12].

Joint pain, joint swelling, locomotion restriction, and joint stiffness are the principal symptoms of OA, while other symptoms like crepitus and joint deformation are also encountered. Recurrent and progressive joint pain, being relieved by rest and worsened with joint exercise, is the most problematic symptom. Although the origin of pain in OA is not fully understood, it may arise from mechanoreceptors and nociceptive fibers in the synovium, capsule, subchondral bone, tendons, periosteum, or ligaments [13].

Recent studies report that the disease burden of OA is comparable to that of rheumatoid arthritis [14, 15]. Globally, a 75% rise was observed in OA-related years lived with disabilities (YLDs) from 1990 to 2013, with OA accounting for 2.4% of all YLDs [16]. Hence, OA represents the third fastest increasing condition related to disability, following dementia and diabetes [16, 17]. In the USA (2010), approximately 10% of all ambulatory care visits were to diagnose arthritis and other rheumatic diseases, 58% of which were estimated to be related to symptomatic OA [18]. The economic burden due to OA comprises three parts: indirect costs such as loss of productivity and disability payments; direct costs like hospital resources, conservative treatment, and research; and intangible costs caused by mental illness and reduced life quality.

Pathophysiology and treatment of osteoarthritis

Multiple pathological processes jointly contribute to the development of OA, and various phenotypes are thus formed [19]. The risk factors for OA development include age, trauma, obesity, innate immunity, metabolic diseases, systemic inflammatory conditions, and genetic predisposition [12, 20]. Currently, low-grade inflammation is the primary focus of OA pathophysiology because the reported risk factors may lead to chronic inflammatory conditions [21]. Another pathological process that might lead to OA is the metabolically triggered inflammation [22]. Metabolic disturbance of nutrients and metabolites leads to oxidative stress and chronic inflammation by inducing adipocytes to release adipokines, C-reactive protein (CRP), complement components, cytokines, and other pro-inflammatory mediators, which may result in cartilage and surrounding tissue destruction. Pro-catabolic and pro-inflammatory mediators, along with mechanical and oxidative stressors, deteriorate the performance and life cycle of chondrocytes, induce hypertrophy, and ultimately make them prone to degenerative responses [19].

While autophagy is reported to preserve chondrocytes, and its loss may contribute to OA development [23], apoptosis also takes place amidst OA development and endochondral ossification [24]. Cartilage degradation products, mainly cartilage wear particles [25], may lead to hyperplasia and hypertrophy of synovial fibroblasts/fibrocytes, which can induce the activation of B and T cells to amplify the inflammation [26, 27]. The inflammatory responses also lead to the activation of macrophages, which release several pro-inflammatory mediators, matrix metalloproteinases, bioactive lipids, neuropeptides, and growth factors. A feedback of cartilage breakdown and synovial inflammation is subsequently induced. However, chondrocytes and synovial tissues also release anti-inflammatory mediators, such as IL-4, IL-10, and IL-13 to modulate the inflammatory responses. Besides, the inflamed synovium can induce angiogenesis and osteophyte formation (Fig. 1).

Fig. 1
figure 1

Overview of the healthy and osteoarthritic joint along with the pathophysiology of OA. A Healthy joint is depicted: intact cartilage with no fissures and synovial inflammation signs. Osteoarthritis is characterized by soft tissue swelling, osteophyte formation, meniscus deterioration, and degeneration of cartilage. B Cartilage breakdown products are released from the damaged cartilage tissue into the joint space, which are phagocytosed by the synovial cells and infiltrated macrophages, intensifying synovial inflammation. In the inflamed synovium, pro-inflammatory and catabolic mediators are produced by the activated synovial cells that cause overproduction of the proteolytic enzymes, establishing a positive feedback loop. The activated synovial B cells, T cells, and infiltrating macrophages amplify the inflammatory response. To neutralize this inflammatory response, anti-inflammatory cytokines are produced by the synoviocytes and chondrocytes. Furthermore, the inflamed macrophages contribute to the synovial angiogenesis and osteophyte formation via VEGF and BMPs release, respectively. Panel B is adapted from Sellam et al. [27] with permission, copyright 2010, Springer Nature. (The figure was prepared with Biorender). ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; BMP, bone morphogenetic protein; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; LTB4, leukotriene B4; MMP, matrix metalloproteinase; NO, nitric oxide; OA, osteoarthritis; PGE2, prostaglandin E2; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor

Currently, there is no licensed drug with valid disease-modifying activity against OA. Hence, the management of OA is targeted at improving disability, pain, and life quality with pharmacologic and non-pharmacologic therapies. The most effective and safest treatment for knee/hip OA is physical exercise/activity coupled with self-management approaches [18, 28]. All OA management guidelines [29,30,31] advocate the promotion of healthy weight and self-management, along with a combination of aerobic and strengthening exercises [32] as core management approaches. Furthermore, systemic or local non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular hyaluronan injection, or intra-articular corticosteroids are frequently administered [28], though with poor long-term outcomes.

Joint replacement is recommended when non-surgical methods cannot control OA symptoms. Nonetheless, joint replacement is not a cure for OA; around 20~30% of knee and hip replacement patients report no or little improvement and are not satisfied with the results of their surgery 1 year post-joint replacement [33, 34]. Worldwide, while scientists continue to work towards a better understanding of the predisposing factors for poor results following knee/hip joint replacement, there remains an urgent need to recognize effective and safe non-surgical modalities to prevent and treat OA.

The use of herbal medicine for analgesic and anti-inflammatory therapy of joint diseases has been practiced for a long time in the form of phytotherapeutic drugs in both the eastern and western worlds. Herbal compounds extracted from traditional Chinese medicine (TCM) plants have been applied for the treatment of multiple diseases, with artemisinin used for the treatment of malaria as the most well-known example (2015 Nobel prize by Youyou Tu). More recently, the chondroprotective and inflammation modulatory effects of herbal extracts or their individual small molecule compounds have been evaluated in preclinical in vitro and in vivo studies [35]. Several herbal compounds with potential disease-modifying activities have been identified. Nevertheless, only few clinical studies have been documented so far. The aim of this literature review is to provide an overview of promising small-molecule compounds with herbal origin and their mechanism of action, as described in preclinical investigations for the prevention or treatment of OA and related pathologies.

Extraction of small molecules from medicinal herbs

The discovery of new natural compounds is of great significance for drug exploitation and development in the treatment of OA. The formulations used in TCM are extremely complex and contain a variety of effective ingredients. To improve drug efficacy, reduce side effects, and explore the pharmacological mechanism, it is important to extract the components and purify them to obtain effective single compounds. In recent years, some new technologies and methods have been developed to extract and isolate the active ingredients of TCM herbs. The application of these technologies not only helps to improve the extraction rate and the purity of active ingredients, but also facilitates the study of structure, pharmacology, and efficacy.

Supercritical fluid extraction is a technology that uses the supercritical fluid as an extractant to isolate and separate the medicinal components in TCM. This method has the advantages of high extraction efficiency, high purification, easy operation, and absence of residual solvent contamination [36, 37]. Supercritical fluid extraction has widely been used in a variety of TCM herbs. Using this method, Huang et al. extracted and separated psoralen and isopsoralen from Psoralea corylifolia [38]. Furthermore, ginkgolic acids from the epicarp of Ginkgo biloba, tautomeric 7-epimeric spiro oxindole alkaloids from Uncaria macrophylla, coumarin from radix Angelicae dahuricae, and chrysophanol from Rheum palmatum were extracted by supercritical fluid extraction [36, 37, 39, 40].

Ultrasound-assisted extraction is an extraction method with the assistance of ultrasonic energy. It mainly uses the cavitation of ultrasonic waves to accelerate the extraction of active ingredients from plants. In addition, secondary effects of ultrasonic waves, including mechanical vibration, emulsification, diffusion, crushing, and chemical effects, can also accelerate the diffusion-based release of the ingredients to be fully mixed with the solvent, which helps to improve the yield of the effective ingredients. Moreover, the ultrasonic crushing process is a physical process without chemical reaction during the extraction, maintaining the bioactivity of components. Ultrasound-assisted extraction is mainly used for the isolation of plant alkaloids, glycosides, and phenolic compounds [41,42,43,44,45,46,47,48,49,50,51].

The high-speed countercurrent chromatography (HSCCC) technique was developed from countercurrent chromatography and is characterized by high purity, good reproducibility, high separation efficiency, and low solvent usage in the extraction of medicinal herbs [52, 53]. It is particularly suitable for the separation of polar compounds. Fang et al. isolated and purified three ecdysteroids with anti-inflammatory effects from the stems of Diploclisia glaucescens by the HSCCC technique [54]. Nine compounds with over 95% purity were obtained by the HSCCC technique from the root of Adenophora tetraphlla [53]. HSCCC was reported as a powerful tool to separate the main compounds from the rhizome of Smilax glabra and was valuable for the preparative separation of compounds with broad K-values and similar structures [55].

Many other extraction methods were also used to extract the small molecules from medicinal herbs due to the extreme complexity of their chemical compositions. As a conventional technique, solvent extraction faces some limitations such as using too much organic solvents, losing some volatile compounds, the possibility of leaving toxic solvent residues in the extract, and low extraction efficiency [56]. Microwave-assisted extraction which heats the solvent in contact with the sample by means of microwave energy is an alternative way of increasing the efficiency of conventional extraction methods to extract target compounds from various raw materials [57]. Ultimately, if the effective constituent in the herbs is identified, successful biochemical synthesis is also a valid option due to its high efficiency.

Therapeutic effects of small molecules: anti-inflammatory, anti-catabolic, and anabolic activity

Inflammatory responses and cartilage matrix degradation play a critical role in the progression of OA. Thus, many scholars have studied and explored small molecules extracted from TCM for interfering with inflammation and degeneration or have modified their structure to make them more effective against OA (Table 1). Curcumin, a polyphenol separated from thye rhizomes of Turmeric and Curcuma longa, was shown to reduce inflammation in knee OA in rats through blocking the TLR4/MyD88/NF-κB signaling pathway [60]. Paeonol, one of the active compounds found in Paeonia lactiflora pallas, Cynanchum paniculatum, and Paeonia suffruticosa, had anti-inflammatory efficacy on IL-1β-stimulated human primary chondrocytes by downregulating the expression of IL-6 and tumor necrosis factor (TNF)-α, thereby inhibiting phosphorylation of IκBα and activation of nuclear factor-κB (NF-κB). It also prevented cartilage matrix degradation by reducing the expression of matrix metalloproteinase (MMP)-3 and MMP-13 and preserving the expression of type II collagen [83]. In human osteoarthritic chondrocytes, vanillic acid showed significant anti-inflammatory properties, which were attributed to an inhibition of phosphorylation in the NF-κB signaling pathway [84].

Table 1 Effect of small molecules extracted from traditional Chinese medicine on osteoarthritis

Anabolic activity is of equal significance since the destruction of the articular cartilage is mainly caused by an imbalance of synthesis and degradation of the extracellular matrix (ECM). Hence, the development of drugs that promote the proliferation of chondrocytes and the formation of ECM, resulting in cartilage regeneration, is another research direction. The small-molecule halofuginone [80] isolated from the plant Dichroa febrifuga lowered proteoglycan loss and calcification of articular cartilage in rodents subjected to anterior cruciate ligament transection (ACLT) compared with vehicle-treated ACLT controls. Besides, halofuginone reduced the expression of collagen X, MMP-13, and ADAMTS-5, while increasing lubricin, collagen II, and aggrecan. Wogonin [85] derived from the root extract of Scutellaria baicalensis exerted chondroprotective effects through suppression of inflammation/oxidative stress (reducing the expression of IL-6, COX-2, PGE2, iNOS, and NO), matrix degradation (lowered the expression of MMP-13, MMP-3, MMP-9, and ADAMTS-4), and stimulation of collagen II and aggrecan expression in OA chondrocytes and cartilage explants. Ligustrazine [65] protected chondrocytes against IL-1β-induced injury presumably by downregulating the expression of IL-1, IL-6, TNF-α, and MMP-13 and by upregulating the expression of collagen II and aggrecan associated with regulation of SOX9 and inactivation of NF-κB. In human osteoarthritic chondrocytes, epimedin C demonstrated significant anabolic effects by increasing the expression of collagenous and non-collagenous matrix proteins, such as cartilage oligomeric matrix protein, and growth factors, including growth differentiation factor 5 and connective tissue growth factor; both vanillic acid and epimedin C also suppressed the MMP activity in the chondrocyte inflammation model [84].

Signaling pathways as therapeutic targets

Generally, with the imbalance between anabolism and catabolism of the articular cartilage, excessive destruction of the ECM results in progressive degeneration. The pathophysiological process of articular cartilage degeneration involves a series of cell signal transduction pathways. Therefore, molecular therapy targeting these signaling pathways is a major research direction (Fig. 2).

Fig. 2
figure 2

Potential therapeutic targets of small molecules with herbal origin in signaling pathways associated with cartilage degeneration. Name of the compounds: (1) polyphenol-rich pomegranate fruit extract, (2) Egb761, (3) polyoxypregnane glycoside, (4) anemonin, (5) hinokitiol, (6) tetrandrine, (7) oxymatrine, (8) polygalacic acid, (9) zingerone, and (10) icariin. As shown above, some of the compounds have multiple signaling targets. (The figure was prepared with Biorender). TNF-α, tumor necrosis factor-α; TNFR1, tumor necrosis factor receptor 1; TRADD, TNF receptor death domain; MAPK, mitogen-activated protein kinase; IL-1β, interleukin-1β; IL-1R, interleukin-1 receptor; IL-1RAcP, interleukin-1 receptor accessory protein; TOLLIP, Toll-interacting protein; NIK, NF-κB inducible kinase; IKKα, IκB kinase α; IKKβ, IκB kinase β; IκB, NF-κB inhibitor; NF-κB, nuclear factor κB; MMPs, matrix metalloproteinases; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; IL-6, interleukin-6; IL-8, interleukin-8; COX-2, cyclooxygenase-2; ROS, reactive oxygen species; TIMPs, tissue inhibitor of metalloproteinases; Col2a1, collagen 2a1

NF-κB signaling pathway

NF-κB is a widely expressed transcription factor family existing ubiquitously in eukaryotic cells, which is associated with the pathogenesis of a number of inflammatory diseases and plays a complex role in different cell types and disease states [86]. The NF-κB family consists of the following five members: RelA (p65), RelB, c-Rel, NF-κB1 (p50 and p105), and NF-κB2 (p52 and p100) [87]. It has been demonstrated that the NF-κB signaling pathway plays a significant role in the course of OA [88]. NF-κB is usually present in the cytoplasm in the form of p56/p50/IκB trimer complexes. Both IκBa and IκBb of the inhibitory IκB protein family are the major regulators of NF-κB activity [89, 90]. Once the cell is stimulated by activating agents, such as cytokines, bacteria/viruses, and stress, IκBα is phosphorylated and degraded rapidly, resulting in the release and nuclear translocation of NF-κB followed by the activation of gene transcription [91].

The NF-κB protein family exists in various cells and is highly expressed in the synovial tissue, cartilage, subchondral bone, joint fluid, and surrounding muscle [92]. NF-κB is involved in almost all pathological processes of OA. Many small molecules of herbal origin can interfere with the development of OA by regulating the NF-κB signaling pathway. Haseeb et al. found that a polyphenol-rich pomegranate fruit extract inhibited the increase in the phosphorylation level of NF-κB p65 in IL-1β induced osteoarthritic chondrocytes [93]. Egb761 extracted from Ginkgo biloba reduced p-NF-κB p65 protein level and prevented the activation of the NF-κB pathway in TNF-α induced human chondrocytes [94]. Polyoxypregnane glycoside from Dregea volubilis extract inhibited the IL-1β-induced expression of MMPs via the suppression of NF-κB in human chondrocytes [95]. Anemonin showed anti-inflammatory, anti-catabolic, and anabolic effects on IL-1β-induced human chondrocytes in vitro, human cartilage explants ex vivo, and in a destabilization of the medial meniscus (DMM)-induced mouse OA model through the suppression of the IL-1β/NF-κB pathway activation [58]. Similarly, RNA sequencing analysis revealed the interference of vanillic acid with NF-κB signaling in human chondrocytes under inflammatory conditions [84].

Wnt/β-catenin signaling pathway

Elevated expression of Wnt/β-catenin has also been observed in OA [96, 97]. Activation of the Wnt/β-catenin signaling pathway can increase the expression of MMPs and aggrecanases (ADAMTS-4 and ADAMTS-5) [98, 99], leading to the degradation of the ECM, which in turn results in the development of OA [100]. However, inhibition of the β-catenin signaling may also cause defects in postnatal cartilage development or even cartilage destruction [101, 102], suggesting that the Wnt/β-catenin signaling pathway may play a dual role in the pathogenesis of OA. To develop effective small molecules for the treatment of OA, the precise regulation of the Wnt/β-catenin signaling pathway should be considered critically.

Hinokitiol is a natural tropolone-related compound found in the heartwood of Cupressaceae plants that has a wide range of biochemical and pharmacological activities, including anti-bacterial [103], anti-tumor [103], and antioxidant capacities [104]. In addition, Li et al. found that hinokitiol also reduced MMP expression by inhibiting Wnt/β-catenin signaling in vitro and in vivo [73]. Tetrandrine purified from the root of Stephania tetrandrine of the Menispermaceae family was also found to alleviate OA pathways in vitro and in vivo via inhibiting Wnt/β-catenin signaling [74].

MAPK signaling pathways

Three MAPK families have been comprehensively characterized, namely extracellular signal-regulated kinase (ERK), C-Jun N-terminal kinase (JNK/SAPK), and p38 Kinase, which is closely related to the pathogenesis of OA [105]. The anti-inflammatory and anti-catabolic effects of oxymatrine and polygalacic acid were mediated via the inhibition of the phosphorylation of ERK, JNK, and p38 related to the MAPK pathways [72, 75]. Zingerone suppressed cartilage degradation by involving the p38 and JNK MAPK signaling pathways [77]. Icariin showed an anti-catabolic effect via inhibiting the phosphorylation of p38 in IL-1β-induced human SW 1353 chondrosarcoma cells and a rat OA model [76].

Other signaling pathways

AMP-activated protein kinase (AMPK), a crucial regulator of energy metabolism, is a heterotrimeric serine/threonine protein kinase comprising a catalytic α-subunit and two regulatory β- and γ-subunits [106, 107]. AMPK is activated by a conserved threonine (THr172) phosphorylation in the α-subunit as a response to decreased cellular AMP/ATP ratio [106, 108]. Activated AMPK is constitutively expressed in normal articular cartilage, while its level is decreased in OA cartilage due to de-phosphorylation caused by either biomechanical injury or inflammatory cytokines like IL-1β and TNF-α [107, 109]. Natural small molecules like butein and quercetin have shown chondroprotective effects via activation of AMPK [110, 111].

Once activated by extracellular molecules, phosphatidylinositol 3-kinase (PI3K) generates phospholipids, activates downstream protein kinase B (Akt), and further phosphorylates mammalian target of rapamycin (mTOR). It has been proved that the PI3K/AKT/mTOR signaling pathway is involved in cartilage degeneration by affecting its extracellular matrix homeostasis, promoting chondrocytes’ inflammatory response, and especially by inhibiting chondrocyte autophagy [112]. Active compounds, extracted from plants such as icariin and β-ecdysterone, have been demonstrated to alleviate OA by activating autophagy through the regulating PI3K/AKT/mTOR signaling pathway [113, 114]. The PI3K/AKT/mTOR and AMPK signaling pathways have interactions via the common downstream target mTOR; however, they own opposed effects on nutrient and energy homeostasis and cell growth [115, 116].

Clinical translation and its challenges

Based on recent search results on studies registered with www.clinicaltrials.gov (02.2021, filter keywords: osteoarthritis, drug), only 3 trials (NCT03375814, NCT03715140, NCT02905799) on small molecules from herbal origin entered clinical research, although there have been many TCM formulas or decoction products tested in clinical trials. Resveratrol decreased advanced glycation end product (AGE)-stimulated expression and activity of MMP-13 and prevented AGE-mediated destruction of collagen II through inhibiting IKK-IκBα-NF-κB and JNK/ERK-AP-1 signaling pathways [59]. It is currently in a phase III clinical trial (NCT02905799) for patients with knee OA.

There are several hurdles to overcome in the translation of herbal compounds into clinics. Firstly, the traditional treatment for OA including regular oral, topic, and intra-articular administration confronts the shortfalls of low bioavailability and severe side effects due to the low stability or solubility of small molecules in serum or synovial fluid. Novel delivery systems need to be introduced to deliver the small molecules to the target site and improve their stability under storage conditions and their bioavailability in vivo. Using exosomes with the target specificity as a delivery vehicle, the anti-inflammatory activity of curcumin on inflammatory cells was enhanced with therapeutic, but not toxic, effects [117]. The synergistic effect of promotion of chondrocyte autophagy via exposure to sinomenium encapsulated by chitosan microspheres and photo-crosslinked gelatin methacrylate hydrogel retarded the progression of surgically induced OA [118]. A combination of celecoxib-loaded liposomes and hyaluronate gel via intra-articular injection was more effective than a single drug in pain control and cartilage protection [119].

Secondly, the quality of raw herbs varies and is difficult to standardize, resulting in a great variation in the content of the main ingredients even with regulated extraction procedures. Thirdly, insufficient representative animal models and preclinical experiments make the in vivo evidence deficient. Fourthly, issues related to pesticide and heavy metal residues have been reported [120]. Fifthly, although there are thousands of compounds identified in medicinal herbs, most of them will be disregarded because of unidentified beneficial effects or amount, while few are determined to have definite pharmaceutical effects. Lastly, certain herbs have potentially toxic effects on the liver and kidneys. For instance, berberine and coumarin have potential hepatotoxicity, and β-escin and aristolochic acid may cause nephrotoxicity [121]. Standardized and comprehensive toxicity studies will be necessary to verify the safety of the compounds for clinical application.

Discussion

The management of OA is unsatisfactory for a significant number of patients who neither respond to the existing conservative treatment nor achieve indications of joint replacement surgery. These include older patients (> 55 years of age) with moderate or younger patients with moderate to severe signs and symptoms of joint degeneration [122]. For these cases, small molecules of herbal origin could represent a promising approach to halt, delay, or even reverse the degenerative process. Indeed, there are several advantages of herbal small-molecule compounds [123, 124]. Firstly, many herbal compounds have the advantages of little side effects [124] making them suitable for long-term treatment [125]; nevertheless, the safety profile of each individual drug needs to be carefully evaluated. Secondly, there is evidence that several compounds have multi-target effects [123], including anti-inflammatory, anti-apoptotic, anti-catabolic, antioxidant, anabolic, and proliferative effects (Table 1). It is conceivable that a combination of potent compounds will have the broadest effect, which may be attractive as an either alternative or complementary treatment to conventional measures [126]. In addition, small molecular compounds of herbal origin have plenty of resources and are generally cost-effective to produce [127].

Nevertheless, despite the positive outcome of preclinical in vitro and in vivo studies, translation towards clinical application is still in its early stage. There are several reasons for this slow-going progress in drug development. In preclinical models, the pathogenesis and progression are standardized and reproducible, while the heterogeneity among patients makes their responses greatly variable. Therefore, it will be important for future clinical studies to classify patients according to their OA stages and phenotypes, which is an emerging field in clinical research [128]. Factors to consider include previous joint trauma, comorbidities like metabolic disorders, clinical manifestations, and eventually the genetic and epigenetic background. Both the limitation of preclinical models and the failure to clinically diagnose OA at the early stage hamper the development of effective therapies.

The delivery of the compounds also needs to be carefully evaluated. Unlike typical biologics, small molecular drugs are in principle suitable for oral application; however, it needs to be evaluated whether the required activity at the joint site can be achieved. On the other hand, the joint space appears to be suitable for intra-articular application [129]. Novel drug delivery systems have been developed to facilitate controlled drug release in intra-articular applications [130]. In the described animal studies, the compounds have primarily been applied intra-articularly, while intraperitoneal and intragastric delivery was also reported (Table 1). This suggests that systemic application may be sufficiently effective for the respective compounds. Topical application in the form of penetrating formulations can also be considered, although it is more challenging to standardize and improve the dosing into the joint. Interestingly, there is evidence from clinical trials for topical comfrey extract [131] as an analgetic treatment in musculoskeletal pain including OA. However, more rigorous, high-quality controlled studies need to be performed to confirm the therapeutic benefit.

Conclusion

In conclusion, small-molecule compounds of herbal origin may have significant potential for the treatment of OA. Advanced techniques are available for efficient isolation and purification of small molecular compounds from herbs. Numerous preclinical studies have elucidated the mechanisms of action and identified the signaling pathways modulated by the individual compounds. For future studies, patient stratification will be essential because of the heterogeneity among people with OA. The therapeutic benefit may be most pronounced if the compounds can be applied at the early stage of OA, when tissue structures are still intact and functional responsive cells are still present in the joint. Controlled clinical trials of high quality will be needed to confirm the beneficial effects demonstrated in the preclinical studies.

Availability of data and materials

All data are included in this article.

Abbreviations

SOD:

Superoxide dismutase

MDA:

Malondialdehyde

DMM:

Destabilization of the medial meniscus

MIA:

Monoiodoacetate

ACLT:

Anterior cruciate ligament transection

SW 1353 cell line:

Human SW 1353 chondrosarcoma cells

LPS:

Lipopolysaccharides

i.a.:

Intra-articular

i.p.:

Intraperitoneal

i.g.:

Intragastric

AGEs:

Advanced glycation end products

AP-1:

Activator protein-1

mPGES:

Microsomal PGE synthase

h-:

Human

OA:

Osteoarthritis

MMP:

Matrix metalloproteinase

ADAMTS:

A disintegrin-like and metalloproteinase with thrombospondin motifs

GAG:

Glycosaminoglycan

References

  1. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163–96.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: estimates from the Global Burden of Disease 2010 Study. Ann Rheum Dis. 2014;73(7):1323–30.

    Article  PubMed  Google Scholar 

  3. Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386(9991):376–87.

    Article  CAS  PubMed  Google Scholar 

  4. Palazzo C, Nguyen C, Lefevre-Colau M-M, Rannou F, Poiraudeau S. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59(3):134–8.

    Article  PubMed  Google Scholar 

  5. Jordan KP, Jöud A, Bergknut C, Croft P, Edwards JJ, Peat G, et al. International comparisons of the consultation prevalence of musculoskeletal conditions using population-based healthcare data from England and Sweden. Ann Rheum Dis. 2014;73(1):212–8.

    Article  PubMed  Google Scholar 

  6. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheum. 2008;58(1):15–25.

    Article  PubMed  Google Scholar 

  7. Palazzo C, Ravaud J-F, Papelard A, Ravaud P, Poiraudeau S. The burden of musculoskeletal conditions. PLoS One. 2014;9(3):e90633.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Birtwhistle R, Morkem R, Peat G, Williamson T, Green ME, Khan S, et al. Prevalence and management of osteoarthritis in primary care: an epidemiologic cohort study from the Canadian Primary Care Sentinel Surveillance Network. CMAJ Open. 2015;3(3):E270.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Prieto-Alhambra D, Judge A, Javaid MK, Cooper C, Diez-Perez A, Arden NK. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis. 2014;73(9):1659–64.

    Article  PubMed  Google Scholar 

  10. Chopra A. The COPCORD world of musculoskeletal pain and arthritis. Rheumatology (Oxford). 2013;52(11):1925-1928.

  11. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: estimates from the Global Burden of Disease 2010 Study. Ann Rheum Dis. 2014;73(7):1323–30.

    Article  PubMed  Google Scholar 

  12. Martel-Pelletier J, Barr AJ, Cicuttini FM, Conaghan PG, Cooper C, Goldring MB, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072.

    Article  PubMed  Google Scholar 

  13. Abhishek A, Doherty M. Diagnosis and clinical presentation of osteoarthritis. Rheumatic Disease Clinics. 2013;39(1):45–66.

    Article  CAS  PubMed  Google Scholar 

  14. El-Haddad C, Castrejon I, Gibson KA, Yazici Y, Bergman MJ, Pincus T. MDHAQ/RAPID3 scores in patients with osteoarthritis are similar to or higher than in patients with rheumatoid arthritis: a cross-sectional study from current routine rheumatology care at four sites. RMD Open. 2017;3(1):e000391.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chua JR, Jamal S, Riad M, Castrejon I, Malfait AM, Block JA, et al. Disease burden in osteoarthritis is similar to that of rheumatoid arthritis at initial rheumatology visit and significantly greater six months later. Arthritis Rheum. 2019;71(8):1276–84.

    Article  CAS  Google Scholar 

  16. Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800.

    Article  Google Scholar 

  17. Vos T, Abajobir AA, Abate KH, Abbafati C, Abbas KM, Abd-Allah F, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211–59.

    Article  Google Scholar 

  18. Hawker GA. Osteoarthritis is a serious disease. Clin Exp Rheumatol. 2019;37(120):S3–6.

    Google Scholar 

  19. Mobasheri A, Batt M. An update on the pathophysiology of osteoarthritis. Ann Phys Rehabil Med. 2016;59(5-6):333–9.

    Article  PubMed  Google Scholar 

  20. Van Spil WE, Kubassova O, Boesen M, Bay-Jensen AC, Mobasheri A. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol. 2019;165:41–8.

    Article  PubMed  CAS  Google Scholar 

  21. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10):580–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang X, Hunter D, Xu J, Ding C. Metabolic triggered inflammation in osteoarthritis. Osteoarthr Cartil. 2015;23(1):22–30.

    Article  CAS  Google Scholar 

  23. Carames B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010;62(3):791–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hughes A, Oxford AE, Tawara K, Jorcyk CL, Oxford JT. Endoplasmic reticulum stress and unfolded protein response in cartilage pathophysiology; contributing factors to apoptosis and osteoarthritis. Int J Mol Sci. 2017;18(3):665.

    Article  PubMed Central  CAS  Google Scholar 

  25. Estell EG, Silverstein AM, Stefani RM, Lee AJ, Murphy LA, Shah RP, et al. Cartilage wear particles induce an inflammatory response similar to cytokines in human fibroblast-like synoviocytes. J Orthop Res. 2019;37(9):1979–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017;19(1):18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6(11):625–35.

    Article  CAS  PubMed  Google Scholar 

  28. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393(10182):1745–59.

    Article  CAS  PubMed  Google Scholar 

  29. McAlindon TE, Bannuru RR, Sullivan M, Arden N, Berenbaum F, Bierma-Zeinstra S, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr Cartil. 2014;22(3):363–88.

    Article  CAS  Google Scholar 

  30. Fernandes L, Hagen KB, Bijlsma JW, Andreassen O, Christensen P, Conaghan PG, et al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis. 2013;72(7):1125–35.

    Article  PubMed  Google Scholar 

  31. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465–74.

    Article  CAS  Google Scholar 

  32. Tanaka R, Ozawa J, Kito N, Moriyama H. Efficacy of strengthening or aerobic exercise on pain relief in people with knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2013;27(12):1059–71.

    Article  PubMed  Google Scholar 

  33. Jones CA, Beaupre LA, Johnston D, Suarez-Almazor ME. Total joint arthroplasties: current concepts of patient outcomes after surgery. Rheum Dis Clin North Am. 2007;33(1):71–86.

    Article  PubMed  Google Scholar 

  34. Woolhead G, Donovan J, Dieppe P. Patient expectations and total joint arthroplasty. J Rheumatol. 2003;30(7):1656.

    PubMed  Google Scholar 

  35. Ziadlou R, Barbero A, Stoddart MJ, Wirth M, Li Z, Martin I, et al. Regulation of inflammatory response in human osteoarthritic chondrocytes by novel herbal small molecules. Int J Mol Sci. 2019;20(22):5745.

    Article  CAS  PubMed Central  Google Scholar 

  36. Yin X, Yang K, Yang L, Ouyang Z, Chen J. Studies on supercritical CO2 fluid extraction for ginkgolic acids in the epicarp of Ginkgo biloba. Zhong Yao Cai. 2003;26(6):428–9.

    PubMed  Google Scholar 

  37. Lo TC, Nian HC, Chiu KH, Wang AY, Wu BZ. Rapid and efficient purification of chrysophanol in Rheum Palmatum LINN by supercritical fluid extraction coupled with preparative liquid chromatography in tandem. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;893-894:101–6.

    Article  CAS  PubMed  Google Scholar 

  38. Huang F, Huang X, Liang W, Ge F, Wu H. Studies on the supercritical CO2 fluid extraction and separation of psoralen, isopsoralen and fatty oils from Psoralea corylifolia. Zhong Yao Cai. 2000;23(5):266–7.

    CAS  PubMed  Google Scholar 

  39. Yang W, Zhang Y, Pan H, Yao C, Hou J, Yao S, et al. Supercritical fluid chromatography for separation and preparation of tautomeric 7-epimeric spiro oxindole alkaloids from Uncaria macrophylla. J Pharm Biomed Anal. 2017;134:352–60.

    Article  CAS  PubMed  Google Scholar 

  40. Liang XL, Liao ZG, Zhu JY, Zhao GW, Yang M, Yin RL, et al. The absorption characterization effects and mechanism of Radix Angelicae dahuricae extracts on baicalin in Radix Scutellariae using in vivo and in vitro absorption models. J Ethnopharmacol. 2012;139(1):52–7.

    Article  PubMed  Google Scholar 

  41. Wang H, Tong Y, Li W, Zhang X, Gao X, Yong J, et al. Enhanced ultrasound-assisted enzymatic hydrolysis extraction of quinolizidine alkaloids from Sophora alopecuroides L. seeds. J Nat Med. 2018;72(2):424–32.

    Article  CAS  PubMed  Google Scholar 

  42. Li Y, Zeng RJ, Lu Q, Wu SS, Chen JZ. Ultrasound/microwave-assisted extraction and comparative analysis of bioactive/toxic indole alkaloids in different medicinal parts of Gelsemium elegans Benth by ultra-high performance liquid chromatography with MS/MS. J Sep Sci. 2014;37(3):308–13.

    Article  PubMed  CAS  Google Scholar 

  43. Tutunchi P, Roufegarinejad L, Hamishehkar H, Alizadeh A. Extraction of red beet extract with beta-cyclodextrin-enhanced ultrasound assisted extraction: a strategy for enhancing the extraction efficacy of bioactive compounds and their stability in food models. Food Chem. 2019;297:124994.

    Article  CAS  PubMed  Google Scholar 

  44. Hossain MB, Tiwari BK, Gangopadhyay N, O’Donnell CP, Brunton NP, Rai DK. Ultrasonic extraction of steroidal alkaloids from potato peel waste. Ultrason Sonochem. 2014;21(4):1470–6.

    Article  CAS  PubMed  Google Scholar 

  45. Patil DM, Akamanchi KG. Ultrasound-assisted rapid extraction and kinetic modelling of influential factors: extraction of camptothecin from Nothapodytes nimmoniana plant. Ultrason Sonochem. 2017;37:582–91.

    Article  CAS  PubMed  Google Scholar 

  46. Yohannes A, Zhang B, Dong B, Yao S. Ultrasonic extraction of tropane alkaloids from Radix physochlainae using as extractant an ionic liquid with similar structure. Molecules. 2019;24(16):2897.

    Article  CAS  PubMed Central  Google Scholar 

  47. Navarro Del Hierro J, Herrera T, Garcia-Risco MR, Fornari T, Reglero G, Martin D. Ultrasound-assisted extraction and bioaccessibility of saponins from edible seeds: quinoa, lentil, fenugreek, soybean and lupin. Food Res Int. 2018;109:440–7.

    Article  CAS  PubMed  Google Scholar 

  48. Espada-Bellido E, Ferreiro-Gonzalez M, Carrera C, Palma M, Barroso CG, Barbero GF. Optimization of the ultrasound-assisted extraction of anthocyanins and total phenolic compounds in mulberry (Morus nigra) pulp. Food Chem. 2017;219:23–32.

    Article  CAS  PubMed  Google Scholar 

  49. He B, Zhang LL, Yue XY, Liang J, Jiang J, Gao XL, et al. Optimization of ultrasound-assisted extraction of phenolic compounds and anthocyanins from blueberry (Vaccinium ashei) wine pomace. Food Chem. 2016;204:70–6.

    Article  CAS  PubMed  Google Scholar 

  50. Nipornram S, Tochampa W, Rattanatraiwong P, Singanusong R. Optimization of low power ultrasound-assisted extraction of phenolic compounds from mandarin (Citrus reticulata Blanco cv. Sainampueng) peel. Food Chem. 2018;241:338–45.

    Article  CAS  PubMed  Google Scholar 

  51. Leichtweis MG, Pereira C, Prieto MA, Barreiro MF, Baraldi IJ, Barros L, et al. Ultrasound as a rapid and low-cost extraction procedure to obtain anthocyanin-based colorants from Prunus spinosa L. fruit epicarp: comparative study with conventional heat-based extraction. Molecules. 2019;24(3):573.

    Article  PubMed Central  CAS  Google Scholar 

  52. Yao S, Li Y, Kong L. Preparative isolation and purification of chemical constituents from the root of Polygonum multiflorum by high-speed counter-current chromatography. J Chromatogr A. 2006;1115(1-2):64–71.

    Article  CAS  PubMed  Google Scholar 

  53. Yao S, Liu R, Huang X, Kong L. Preparative isolation and purification of chemical constituents from the root of Adenophora tetraphlla by high-speed counter-current chromatography with evaporative light scattering detection. J Chromatogr A. 2007;1139(2):254–62.

    Article  CAS  PubMed  Google Scholar 

  54. Fang L, Li J, Zhou J, Wang X, Guo L. Isolation and purification of three ecdysteroids from the stems of Diploclisia glaucescens by high-speed countercurrent chromatography and their anti-inflammatory activities in vitro. Molecules. 2017;22(8):1310.

    Article  PubMed Central  CAS  Google Scholar 

  55. Guo W, Dong H, Wang D, Yang B, Wang X, Huang L. Separation of seven polyphenols from the rhizome of Smilax glabra by offline two dimension recycling HSCCC with extrusion mode. Molecules. 2018;23(2):505.

    Article  PubMed Central  CAS  Google Scholar 

  56. Azmir J, Zaidul ISM, Rahman M, Sharif K, Mohamed A, Sahena F, et al. Techniques for extraction of bioactive compounds from plant materials: a review. J Food Eng. 2013;117(4):426–36.

    Article  CAS  Google Scholar 

  57. Rahath Kubra I, Kumar D, Jagan Mohan Rao L. Emerging trends in microwave processing of spices and herbs. Crit Rev Food Sci Nutr. 2016;56(13):2160–73.

    Article  CAS  PubMed  Google Scholar 

  58. Wang Z, Huang J, Zhou S, Luo F, Xu W, Wang Q, et al. Anemonin attenuates osteoarthritis progression through inhibiting the activation of IL-1beta/NF-kappaB pathway. J Cell Mol Med. 2017;21(12):3231–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu FC, Hung LF, Wu WL, Chang DM, Huang CY, Lai JH, et al. Chondroprotective effects and mechanisms of resveratrol in advanced glycation end products-stimulated chondrocytes. Arthritis Res Ther. 2010;12(5):R167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Zhang Y, Zeng Y. Curcumin reduces inflammation in knee osteoarthritis rats through blocking TLR4 /MyD88/NF-kappaB signal pathway. Drug Dev Res. 2019;80(3):353–9.

    Article  CAS  PubMed  Google Scholar 

  61. Ma P, Yue L, Yang H, Fan Y, Bai J, Li S, et al. Chondroprotective and anti-inflammatory effects of amurensin H by regulating TLR4/Syk/NF-kappaB signals. J Cell Mol Med. 2020;24(2):1958–68.

    Article  CAS  PubMed  Google Scholar 

  62. Lou Y, Wang C, Tang Q, Zheng W, Feng Z, Yu X, et al. Paeonol inhibits IL-1beta-induced inflammation via PI3K/Akt/NF-kappaB pathways: in vivo and vitro studies. Inflammation. 2017;40(5):1698–706.

    Article  CAS  PubMed  Google Scholar 

  63. Xie L, Xie H, Chen C, Tao Z, Zhang C, Cai L. Inhibiting the PI3K/AKT/NF-kappaB signal pathway with nobiletin for attenuating the development of osteoarthritis: in vitro and in vivo studies. Food Funct. 2019;10(4):2161–75.

    Article  CAS  PubMed  Google Scholar 

  64. Xia T, Gao R, Zhou G, Liu J, Li J, Shen J. Trans-cinnamaldehyde inhibits IL-1beta-stimulated inflammation in chondrocytes by suppressing NF-kappaB and p38-JNK pathways and exerts chondrocyte protective effects in a rat model of osteoarthritis. Biomed Res Int. 2019;2019:4039472.

    PubMed  PubMed Central  Google Scholar 

  65. Yu T, Qu J, Wang Y, Jin H. Ligustrazine protects chondrocyte against IL-1beta induced injury by regulation of SOX9/NF-kappaB signaling pathway. J Cell Biochem. 2018;119(9):7419–30.

    Article  CAS  PubMed  Google Scholar 

  66. Ying X, Chen X, Cheng S, Shen Y, Peng L, Xu HZ. Piperine inhibits IL-beta induced expression of inflammatory mediators in human osteoarthritis chondrocyte. Int Immunopharmacol. 2013;17(2):293–9.

    Article  CAS  PubMed  Google Scholar 

  67. Ding Q, Zhong H, Qi Y, Cheng Y, Li W, Yan S, et al. Anti-arthritic effects of crocin in interleukin-1beta-treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflamm Res. 2013;62(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  68. Yin W, Lei Y. Leonurine inhibits IL-1beta induced inflammation in murine chondrocytes and ameliorates murine osteoarthritis. Int Immunopharmacol. 2018;65:50–9.

    Article  CAS  PubMed  Google Scholar 

  69. Lin J, Li X, Qi W, Yan Y, Chen K, Xue X, et al. Isofraxidin inhibits interleukin-1beta induced inflammatory response in human osteoarthritis chondrocytes. Int Immunopharmacol. 2018;64:238–45.

    Article  CAS  PubMed  Google Scholar 

  70. Chen X, Zhang C, Wang X, Huo S. Juglanin inhibits IL-1beta-induced inflammation in human chondrocytes. Artif Cells Nanomed Biotechnol. 2019;47(1):3614–20.

    Article  CAS  PubMed  Google Scholar 

  71. Luo Z, Hu Z, Bian Y, Su W, Li X, Li S, et al. Scutellarin attenuates the IL-1beta-induced inflammation in mouse chondrocytes and prevents osteoarthritic progression. Front Pharmacol. 2020;11:107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jiang Y, Sang W, Wang C, Lu H, Zhang T, Wang Z, et al. Oxymatrine exerts protective effects on osteoarthritis via modulating chondrocyte homoeostasis and suppressing osteoclastogenesis. J Cell Mol Med. 2018;22(8):3941–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li J, Zhou XD, Yang KH, Fan TD, Chen WP, Jiang LF, et al. Hinokitiol reduces matrix metalloproteinase expression by inhibiting Wnt/beta-catenin signaling in vitro and in vivo. Int Immunopharmacol. 2014;23(1):85–91.

    Article  PubMed  CAS  Google Scholar 

  74. Zhou X, Li W, Jiang L, Bao J, Tao L, Li J, et al. Tetrandrine inhibits the Wnt/beta-catenin signalling pathway and alleviates osteoarthritis: an in vitro and in vivo study. Evid Based Complement Alternat Med. 2013;2013:809579.

    PubMed  PubMed Central  Google Scholar 

  75. Xu K, Ma C, Xu L, Ran J, Jiang L, He Y, et al. Polygalacic acid inhibits MMPs expression and osteoarthritis via Wnt/beta-catenin and MAPK signal pathways suppression. Int Immunopharmacol. 2018;63:246–52.

    Article  CAS  PubMed  Google Scholar 

  76. Zeng L, Wang W, Rong XF, Zhong Y, Jia P, Zhou GQ, et al. Chondroprotective effects and multi-target mechanisms of Icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model. Int Immunopharmacol. 2014;18(1):175–81.

    Article  CAS  PubMed  Google Scholar 

  77. Ruangsuriya J, Budprom P, Viriyakhasem N, Kongdang P, Chokchaitaweesuk C, Sirikaew N, et al. Suppression of cartilage degradation by Zingerone involving the p38 and JNK MAPK signaling pathway. Planta Med. 2017;83(3-04):268–76.

    CAS  PubMed  Google Scholar 

  78. Chen Y, Shou K, Gong C, Yang H, Yang Y, Bao T. Anti-inflammatory effect of geniposide on osteoarthritis by suppressing the activation of p38 MAPK signaling pathway. Biomed Res Int. 2018;2018:8384576.

    PubMed  PubMed Central  Google Scholar 

  79. Wang W, Zeng L, Wang ZM, Zhang S, Rong XF, Li RH. Ginsenoside Rb1 inhibits matrix metalloproteinase 13 through down-regulating Notch signaling pathway in osteoarthritis. Exp Biol Med (Maywood). 2015;240(12):1614–21.

    Article  CAS  Google Scholar 

  80. Cui Z, Crane J, Xie H, Jin X, Zhen G, Li C, et al. Halofuginone attenuates osteoarthritis by inhibition of TGF-beta activity and H-type vessel formation in subchondral bone. Ann Rheum Dis. 2016;75(9):1714–21.

    Article  CAS  PubMed  Google Scholar 

  81. Wang W, Ha C, Lin T, Wang D, Wang Y, Gong M. Celastrol attenuates pain and cartilage damage via SDF-1/CXCR4 signalling pathway in osteoarthritis rats. J Pharm Pharmacol. 2018;70(1):81–8.

    Article  CAS  PubMed  Google Scholar 

  82. Khan NM, Ahmad I, Ansari MY, Haqqi TM. Wogonin, a natural flavonoid, intercalates with genomic DNA and exhibits protective effects in IL-1beta stimulated osteoarthritis chondrocytes. Chem Biol Interact. 2017;274:13–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang Q, Xu X, Kang Z, Zhang Z, Li Y. Paeonol prevents IL-1beta-induced inflammatory response and degradation of type II collagen in human primary chondrocytes. Artif Cells Nanomed Biotechnol. 2019;47(1):2139–45.

    Article  CAS  PubMed  Google Scholar 

  84. Ziadlou R, Barbero A, Martin I, Wang X, Qin L, Alini M, Grad S. Anti-Inflammatory and Chondroprotective Effects of Vanillic Acid and Epimedin C in Human Osteoarthritic Chondrocytes. Biomolecules. 2020;10(6):932.

  85. Khan NM, Haseeb A, Ansari MY, Devarapalli P, Haynie S, Haqqi TM. Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human osteoarthritis chondrocytes. Free Radic Biol Med. 2017;106:288–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther. 2017;2:e17023.

    Article  Google Scholar 

  87. Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693–733.

    Article  CAS  PubMed  Google Scholar 

  88. Marcu KB, Otero M, Olivotto E, Borzi RM, Goldring MB. NF-kappaB signaling: multiple angles to target OA. Curr Drug Targets. 2010;11(5):599–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002;109(Suppl):S81–96.

    Article  CAS  PubMed  Google Scholar 

  90. Silverman N, Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev. 2001;15(18):2321–42.

    Article  CAS  PubMed  Google Scholar 

  91. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621–63.

    Article  CAS  PubMed  Google Scholar 

  92. Tanimoto M, Koshino T, Takagi T, Hayashi T, Saito T. Quantitative analysis of NF-kappaB-expression in cartilage and synovium of rat knee induced by intra-articular injection of synthetic lipid A. Inflamm Res. 2002;51(7):357–62.

    Article  CAS  PubMed  Google Scholar 

  93. Haseeb A, Khan NM, Ashruf OS, Haqqi TM. A polyphenol-rich pomegranate fruit extract suppresses NF-kappaB and IL-6 expression by blocking the activation of IKKbeta and NIK in primary human chondrocytes. Phytother Res. 2017;31(5):778–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang X, Zhao X, Tang S. Inhibitory effects of EGb761 on the expression of matrix metalloproteinases (MMPs) and cartilage matrix destruction. Cell Stress Chaperones. 2015;20(5):781–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Itthiarbha A, Phitak T, Sanyacharernkul S, Pothacharoen P, Pompimon W, Kongtawelert P. Polyoxypregnane glycoside from Dregea volubilis extract inhibits IL-1beta-induced expression of matrix metalloproteinase via activation of NF-kappaB in human chondrocytes. In Vitro Cell Dev Biol Anim. 2012;48(1):43–53.

    Article  CAS  PubMed  Google Scholar 

  96. Blom AB, Brockbank SM, van Lent PL, van Beuningen HM, Geurts J, Takahashi N, et al. Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum. 2009;60(2):501–12.

    Article  CAS  PubMed  Google Scholar 

  97. Ryu JH, Kim SJ, Kim SH, Oh CD, Hwang SG, Chun CH, et al. Regulation of the chondrocyte phenotype by beta-catenin. Development. 2002;129(23):5541–50.

    CAS  PubMed  Google Scholar 

  98. Wang M, Sampson ER, Jin H, Li J, Ke QH, Im HJ, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther. 2013;15(1):R5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yuasa T, Otani T, Koike T, Iwamoto M, Enomoto-Iwamoto M. Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration. Lab Invest. 2008;88(3):264–74.

    Article  CAS  PubMed  Google Scholar 

  100. Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, et al. Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res. 2009;24(1):12–21.

    Article  CAS  PubMed  Google Scholar 

  101. Chen M, Zhu M, Awad H, Li TF, Sheu TJ, Boyce BF, et al. Inhibition of beta-catenin signaling causes defects in postnatal cartilage development. J Cell Sci. 2008;121(Pt 9):1455–65.

    Article  CAS  PubMed  Google Scholar 

  102. Zhu M, Chen M, Zuscik M, Wu Q, Wang YJ, Rosier RN, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008;58(7):2053–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Arima Y, Nakai Y, Hayakawa R, Nishino T. Antibacterial effect of beta-thujaplicin on staphylococci isolated from atopic dermatitis: relationship between changes in the number of viable bacterial cells and clinical improvement in an eczematous lesion of atopic dermatitis. J Antimicrob Chemother. 2003;51(1):113–22.

    Article  CAS  PubMed  Google Scholar 

  104. Liu S, Yamauchi H. p27-Associated G1 arrest induced by hinokitiol in human malignant melanoma cells is mediated via down-regulation of pRb, Skp2 ubiquitin ligase, and impairment of Cdk2 function. Cancer Lett. 2009;286(2):240–9.

    Article  CAS  PubMed  Google Scholar 

  105. Chun JS. Expression, activity, and regulation of MAP kinases in cultured chondrocytes. Methods Mol Med. 2004;100:291–306.

    CAS  PubMed  Google Scholar 

  106. Witczak CA, Sharoff CG, Goodyear LJ. AMP-activated protein kinase in skeletal muscle: from structure and localization to its role as a master regulator of cellular metabolism. Cell Mol Life Sci. 2008;65(23):3737–55.

    Article  CAS  PubMed  Google Scholar 

  107. June RK, Liu-Bryan R, Long F, Griffin TM. Emerging role of metabolic signaling in synovial joint remodeling and osteoarthritis. J Orthop Res. 2016;34(12):2048–58.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Zheng L, Zhang Z, Sheng P, Mobasheri A. The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis. Ageing Res Rev. 2021;66:101249.

    Article  CAS  PubMed  Google Scholar 

  109. Terkeltaub R, Yang B, Lotz M, Liu-Bryan R. Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1beta and tumor necrosis factor alpha. Arthritis Rheum. 2011;63(7):1928–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ansari MY, Ahmad N, Haqqi TM. Butein activates autophagy through AMPK/TSC2/ULK1/mTOR pathway to inhibit IL-6 expression in IL-1beta stimulated human chondrocytes. Cell Physiol Biochem. 2018;49(3):932–46.

    Article  CAS  PubMed  Google Scholar 

  111. Feng K, Chen Z, Pengcheng L, Zhang S, Wang X. Quercetin attenuates oxidative stress-induced apoptosis via SIRT1/AMPK-mediated inhibition of ER stress in rat chondrocytes and prevents the progression of osteoarthritis in a rat model. J Cell Physiol. 2019;234(10):18192–205.

    Article  CAS  PubMed  Google Scholar 

  112. Sun K, Luo J, Guo J, Yao X, Jing X, Guo F. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthr Cartil. 2020;28(4):400–9.

    Article  CAS  Google Scholar 

  113. Tang Y, Mo Y, Xin D, Zeng L, Yue Z, Xu C. β-Ecdysterone alleviates osteoarthritis by activating autophagy in chondrocytes through regulating PI3K/AKT/mTOR signal pathway. Am J Transl Res. 2020;12(11):7174–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Tang Y, Li Y, Xin D, Chen L, Xiong Z, Yu X. Icariin alleviates osteoarthritis by regulating autophagy of chondrocytes by mediating PI3K/AKT/mTOR signaling. Bioengineered. 2021;12(1):2984–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gonzalez A, Hall MN, Lin SC, Hardie DG. AMPK and TOR: the yin and yang of cellular nutrient sensing and growth control. Cell Metab. 2020;31(3):472–92.

    Article  CAS  PubMed  Google Scholar 

  116. Yi D, Yu H, Lu K, Ruan C, Ding C, Tong L, et al. AMPK signaling in energy control, cartilage biology, and osteoarthritis. Front Cell Dev Biol. 2021;9:696602.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18(9):1606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chen P, Xia C, Mei S, Wang J, Shan Z, Lin X, et al. Intra-articular delivery of sinomenium encapsulated by chitosan microspheres and photo-crosslinked GelMA hydrogel ameliorates osteoarthritis by effectively regulating autophagy. Biomaterials. 2016;81:1–13.

    Article  CAS  PubMed  Google Scholar 

  119. Dong J, Jiang D, Wang Z, Wu G, Miao L, Huang L. Intra-articular delivery of liposomal celecoxib-hyaluronate combination for the treatment of osteoarthritis in rabbit model. Int J Pharm. 2013;441(1-2):285–90.

    Article  CAS  PubMed  Google Scholar 

  120. Efferth T, Kaina B. Toxicities by herbal medicines with emphasis to traditional Chinese medicine. Curr Drug Metab. 2011;12(10):989–96.

    Article  CAS  PubMed  Google Scholar 

  121. Xu X, Zhu R, Ying J, Zhao M, Wu X, Cao G, et al. Nephrotoxicity of herbal medicine and its prevention. Front Pharmacol. 2020;11:569551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Watt FE, Gulati M. New drug treatments for osteoarthritis: what is on the horizon? Eur Med J Rheumatol. 2017;2(1):50–8.

    PubMed  PubMed Central  Google Scholar 

  123. Li H. Advances in anti hepatic fibrotic therapy with traditional Chinese medicine herbal formula. J Ethnopharmacol. 2020;251:112442.

    Article  CAS  PubMed  Google Scholar 

  124. Long Y, Yang Q, Xiang Y, Zhang Y, Wan J, Liu S, et al. Nose to brain drug delivery - a promising strategy for active components from herbal medicine for treating cerebral ischemia reperfusion. Pharmacol Res. 2020;159:104795.

    Article  CAS  PubMed  Google Scholar 

  125. Sharifi-Rad J, Rayess YE, Rizk AA, Sadaka C, Zgheib R, Zam W, et al. Turmeric and its major compound curcumin on health: bioactive effects and safety profiles for food, pharmaceutical, biotechnological and medicinal applications. Front Pharmacol. 2020;11:01021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Steinmeyer J, Bock F, Stove J, Jerosch J, Flechtenmacher J. Pharmacological treatment of knee osteoarthritis: special considerations of the new German guideline. Orthop Rev (Pavia). 2018;10(4):7782.

    Article  Google Scholar 

  127. Kamali A, Ziadlou R, Lang G, Pfannkuche J, Cui S, Li Z, et al. Small molecule-based treatment approaches for intervertebral disc degeneration: current options and future directions. Theranostics. 2021;11(1):27–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mobasheri A, Saarakkala S, Finnila M, Karsdal MA, Bay-Jensen AC, van Spil WE. Recent advances in understanding the phenotypes of osteoarthritis. F1000Res 2019, 8:F1000 Faculty Rev-2091.

  129. Jones IA, Togashi R, Wilson ML, Heckmann N, Vangsness CT Jr. Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol. 2019;15(2):77–90.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Maudens P, Jordan O, Allemann E. Recent advances in intra-articular drug delivery systems for osteoarthritis therapy. Drug Discov Today. 2018;23(10):1761–75.

    Article  CAS  PubMed  Google Scholar 

  131. Frost R, MacPherson H, O’Meara S. A critical scoping review of external uses of comfrey (Symphytum spp.). Complement Ther Med. 2013;21(6):724–45.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Open access funding provided by Swiss Federal Institute of Technology Zurich This work was funded by the AO Foundation and AOSpine International.

Author information

Authors and Affiliations

Authors

Contributions

PZ, AK, RZ, PA, VB, ZL, and SG performed the concept and design of the article. PZ, KL, XW, RGR, MA, VB, ZL, and SG analyzed and interpreted the data. PZ, KL, AK, PA, VB, ZL, and SG drafted the article. RZ, XW, RGR, MA, ZL, and SG critically reviewed the article. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhen Li or Sibylle Grad.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, P., Li, K., Kamali, A. et al. Small molecules of herbal origin for osteoarthritis treatment: in vitro and in vivo evidence. Arthritis Res Ther 24, 105 (2022). https://doi.org/10.1186/s13075-022-02785-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13075-022-02785-y

Keywords