Introduction

Osteoarthritis (OA) is the most common type of arthritis, characterized by pain, stiffness, and loss of function in the joints. Although the etiology of OA is still unknown, epidemiologic reports and studies suggest a crucial role for both genetic and environmental factors in the causation of the disease. The fundamental aspect of OA pathogenesis is articular cartilage destruction caused by chronic inflammation [1–3]. OA is among the ten most disabling diseases in industrialized countries [4]. Prevalence studies showed that OA is strongly age-dependent, being less common before 40, but rising in frequency with age, such that most people older than 65 show some radiographic evidence of OA in at least one or more joints [5].

Various biological factors are involved in the pathogenesis of OA. Several anabolic and catabolic mediators play key roles in the homeostasis of articular cartilage, resulting in the progression of OA [3]. Pain is particularly important and is thought to be the most noticeable and disabling clinical symptom of OA [6].

Recently, several distinct molecular mechanisms that are possibly commensurate with OA pathogenesis have been identified. Although several pharmacotherapeutic choices that inhibit one or more processes in the pathogenesis of OA are under evaluation for their potential to alter the degenerative process, a complete cure for the disease has not yet been found. Hence, developing more effective therapies is an immediate and important challenge.

This review discusses the potential effects of herbal medicine on joint health based on cell, animal, and human studies along with the possible molecular mechanisms. For thousands of years, many ancient civilizations and cultures have used and refined herbal extracts for treating a variety of joint pains. Indeed, many of the antioxidant, anti-inflammatory, and pain analgesic drugs in our current pharmacopoeia have long established roots in ethnopharmacology. In this review, the most up-to-date information and trends in this area are highlighted. Additionally, we attempted to emphasize the mechanistic aspects targeting pathological pathways involved in OA.

Pathophysiological processes in osteoarthritis that could be favorably targeted by herbal medicines

Inflammation and synovitis

OA is characterized by limited intra-articular inflammation, inflammation of the synovium, and articular degeneration. Synovitis occurs in both the early and late phases of OA and is one of the main contributors to cartilage matrix destruction. Synovitis is associated with the progression of cartilage damage and also increased pain severity [7].

Inflammation in OA also affects the subchondral bone in the zone of calcified cartilage, which invades the deep hyaline cartilage layer. There is ample evidence suggesting a role of pro-inflammatory cytokines especially tumor necrosis factor (TNF) and interleukin-1β (IL-1β) in the inflammatory response of OA [8]. Pro-inflammatory cytokines such as IL-1, IL-8, and TNF-α can stimulate cyclooxygenase-2 (COX-2), and nitric oxide synthase (NOS), especially the inducible isoform of NOS (iNOS) expression. COX-2 and iNOS overexpression can cause overproduction of their products including NO and prostaglandin E2 (PGE2) [9, 10]. These cytokines can stimulate joint damaging cytokines, including granulocyte–monocyte colony-stimulating factor and IL-6, released by macrophages and synoviocytes [9]. Moreover, activation of proteolytic enzymes, including matrix metalloproteinases (MMPs) and collagenases, promotes cartilage breakdown causing synovitis. Pro-inflammatory cytokines inhibit the synthesis of proteoglycans and collagen, increasing their degradation. Thus, cartilage degeneration creates a vicious circle further inducing synovial inflammation [11–13]. Furthermore, several studies highlight the contribution of TNF, IL-1β, and IL-8 in nociceptive pathways in OA by the production of eicosanoids and sympathetic amines [14].

Oxidative damage

“Reactive oxidative species” (ROS) is an inescapable consequence of vital processes, particulary aerobic metabolism. Any metabolic alteration in the production of ROS that exceeds their catabolism can lead to increased oxidant-derived tissue injury or oxidative stress [15, 16].

Several clinical and experimental studies document the important physiological role of oxidative stress in chondrocytes, i.e., chondrocytes are potent source of ROS [16]. There is ample evidence suggesting the role of ROS overproduction in inflammation signaling, pain nociception, and destruction of aging in osteoarthritic cartilage [3, 17]. Indeed, patients with chondral and meniscal lesions demonstrate increased levels of ROS including oxygen ions, superoxide radicals, peroxides, hydroxyl radicals, and hydrogen peroxides, which is originated from oxidative burst mediated by the NADPH oxidase system, in their synovial fluids [3, 16, 17]. Recent studies suggest the involvement of mechanical stress-induced ROS formation in the pathogenesis of OA. Furthermore, oxidative stress may play a crucial role in linking aging with OA [3, 16, 17].

On the other hand, extensive and multilayered antioxidant defense systems containing definite proteins of oxidative stress signaling pathways and antioxidative enzymes such as glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) as well as redox-sensitive transcription factor which regulates redox homeostasis, nuclear factor erythroid 2-related factor 2 (Nrf2), are present in the human body [3, 16, 17, 38]. Furthermore, dietary intake might have a crucial role in the concentrations of antioxidants in the blood. It is also plausible that a high intake of dietary antioxidants may exert alleviating properties in OA [3, 11, 17].

Pain mediators

Cartilage degradation is often attended by pain and physical dysfunction. Arthritic pain due to OA is one of the most disabling symptoms among chronic arthritic conditions. Pain is the most noticeable and disabling clinical symptom of OA, often accompanied by less than optimal functional outcome with reduced quality of life [6]. A combination of sensory, affective, and cognitive processes reflecting impaired cellular mechanisms at both peripheral and central levels of the nervous system maybe at the root of the pain seen in OA [3, 18, 19]. Nociceptors are widely distributed throughout the joint structure including the joint capsule, ligaments, periosteum, and subchondral bone [20].

Damage of the joint cartilage and synovia influences nociceptors located throughout the joint. Peripheral afferent neurons are affected by injury. These triggers are transferred through dorsal root ganglion neurons to the cortical center for processing. This process causes symptomatic pain via central and peripheral sensitization [19, 21]. Moreover, chronic pain in OA may be perpetuated by non-nociceptive factors such as neuropathic component as the result of peripheral inflammation and central sensitization [22].

There is ample evidence suggesting the contribution of central and peripheral pathways in the OA pain mechanism. Indeed, intra-articular anesthetic injections in osteoarthritic hip and knee joints alleviate only 60–80 % of the pain present, depending on the affected joints [23, 24].

In some cases, impaired central mechanisms such as a dysfunction of the descending inhibitory control or an altered cortical processing of noxious information may also contribute to the pain present in OA [25].

Furthermore, mounting evidences suggest several mediators directly or indirectly contribute to the hyperalgesia in OA, which can be categorized into inflammatory mediators (TNF, IL-1, 6, 17, prostanoids and PGE2, NGF, EGF, VEGF, and FGF-2), signaling mediators (NF-κB, ERK1/2, JNK, TLRs, and iNOS), and proteases (MMP-1,3,9, and 13) [3, 6].

Herbal medicine

A large number of herbal medicines have traditionally been used for the management of OA. Many patients suffering from OA symptoms prefer herbal treatment. Traditional medicines all over the world encompass a wide range of herbal remedies in the healing of symptomatologies related to various disorders. Therefore, it is important to evaluate the safety and efficacy of herbal medicines and plant extracts that are taken orally or applied topically for the treatment for OA [26, 27]. In this regard, it would be useful to study the phytochemical active components of herbs and plants in order to develop potentially novel therapies for the treatment for OA. Our review was conducted to evaluate medicinal herbs considered anti-arthritic agents, collect evidence for their potential efficacy addressing when possible their pharmacological mechanisms in an effort to clarify their potential use for the management of OA in the scientific literature.

As shown in Table 1, various herbs have been traditionally used for OA. Also, their plant family and vernacular names are listed. Following are the molecular and biological mechanisms of action of medicinal plants and their active phytochemical agents.

Table 1 Medicinal plants used traditionally for the treatment for OA
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Achillea millefolium

A. millefolium demonstrates in vitro anti-inflammatory activity by decreasing HNE and inhibiting MMP-2 and 9 (Table 2) [28]. A. ageratum and A. santolina exhibit anti-inflammatory activity in vivo by decreasing IL-6, MPO level, and suppressing neutrophil migration into inflamed tissue [29, 30]. A. fragrantissima shows anti-inflammatory activity by decreasing MMP-9 levels and inhibiting IL-1β, COX-2, NO, iNOS, and TNFα production [31]. Stigmasterol, beta-sitosterol, and dicaffeoylquinic acids are the main active components [28, 30].

Table 2 In vitro studies of medicinal plants used in the treatment for OA
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Acorus calamus L

The leaves show anti-inflammatory activity in vitro by decreasing IL-8 and IL-6 with inhibition of NF-κB production. Furthermore, the roots exhibited analgesic activity by inhibiting PG and bradykinin production [32, 33]. The anti-inflammatory activity of A. gramineus is attributed to the reduction of NO activity, inhibiting iNOS expression. Surinamensinols and acoramol are the responsible compounds [32].

Allium sativum

A. sativum demonstrates anti-inflammatory activity in vitro by decreasing various pro-inflammatory mediators [34]. A. flavum showed anti-inflammatory action by decreasing COX-1 and 12-LOX levels [35]. Glucopyranosides, allivictoside, various phenolics, and some allyl derivative compounds are responsible for their anti-inflammatory action [36].

Aloe spp

Anti-inflammatory function of A. barbadensis is attributed to the inhibition of TNF-α and IL-1β level [37]. Researchers have shown that A. vera possesses anti-inflammatory activity by decreasing PLA2 and MMP-9 level [38–40].

Althaea officinalis

A. officinalis and A. rosea exhibit anti-inflammatory and analgesic activities in animal models [41, 42]. Furthermore, A. rosea demonstrated anti-inflammatory action by blocking PGE release from inflamed tissue [42].

Anethum graveloens

The flowers exhibited anti-inflammatory activity in vitro by decreasing NO, iNOS, IL-1β, IL-6, and NF-κB activity. Moreover, the seeds showed similar action in animal models, as well as anti-nociceptive activity [43, 44].

Boswellia carterii and B. serrata

B. carterii decreases CFA-induced edema by suppressing TNF-α and IL-1β levels in animal models. An analgesic action has been proven [45]. In addition, an anti-inflammatory effect of B. serrata by suppressing pro-inflammatory mediators has been reported with 12-ursene 2-diketone being the responsible compound [46]. In a clinical trial, administration of oleo-gum resin of B. serrata in patients with OA of the knee resulted in reduction in knee pain and swelling along with improvement of knee flexion and walking distance as compared to placebo; here, boswellic acid derivatives seem the main biological components [47].

Capparis spp

C. spinosa can inhibit CFA-induced arthritis in rats. Table 3 shows the main active constituents responsible for this function [48, 49]. Also, C. ovata suppresses paw edema by decreasing COX in mice. Moreover, its analgesic activity has been confirmed in an animal model [50, 51].

Table 3 In vivo studies of medicinal plants used for the treatment for OA
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Cassia spp

C. alata decreases CFA-induced arthritis with the suppression of cartilage degradation in the knee joint, decreasing swelling and suppressing leukocyte infiltration in the synovial fluid in an animal model [52]. C. siamea and C. occidentalis demonstrate anti-inflammatory activity in mice by decreasing MDA [53]. Moreover, the analgesic activity of C. siamea has been proven in an animal model [54].

Cinnamomum zeylanicum and C. cassia

C. cassia demonstrates anti-inflammatory activity in vitro and in vivo by suppressing pro-inflammatory mediators and enhancing antioxidant enzymes [55, 56]. Furthermore, C. zeylanicum suppresses paw edema and CFA-induced arthritis in animals [57].

Colchicum autumnale

C. luteum shows anti-inflammatory activity by suppressing TNF-α, IL-6, and IL-1β. It also inhibits CFA- and formaldehyde-induced arthritis in rats [58, 59].

Commiphora myrrha

It shows anti-inflammatory activity suppressing PGE2 and NO production in animal models. Moreover, its analgesic action has been proven in vivo. Table 3 shows the possible biological active constituents [60]. C. mukul demonstrates anti-inflammatory activity by decreasing IFN-γ, IL-12, TNF-α, IL-1β, and NO level [61].

Curcuma zedoaria

The rhizomes possess anti-inflammatory properties as well as anti-arthritis activity with inhibition of joint swelling in animal models, with furanodiene and furanodien one being the active components [62, 63]. C. comosa shows anti-inflammatory activity by suppressing IL-1β, TNF-α, and NF-κB level; here, the diarylheptanoids are the effective compounds [64].

Elaeagnus angustifolia

An anti-inflammatory and analgesic function of these fruits has been demonstrated in animal models [65]. The anti-inflammatory potential of E. oldhamii seems to be by suppressing NO, IL-1β, IL-6, TNF-α, and COX-2 level [66].

Hypericum perforatum

An anti-inflammatory activity of the crude extract with its active components being pseudohypericin, amentoflavone, quercetin, hypericin, hyperoside, epicatechin, and chlorogenic acid has been proven in in vitro and in vivo studies; the potential-related mechanism seems suppression of various pro-inflammatory mediators [67–69]. In addition, Sánchez-Mateo et al. [70] reported that H. reflexum possesses analgesic activity in vivo as well.

Linum usitatissimum L

The seeds exhibit analgesic action. They suppress inflammation by reducing COX and LOX. Kaithwas et al. reported that the anti-arthritic effects of the plant and its active component, α-linolenic acid, are due to diminishing joint edema by decreasing PGE2, LT-B4 in animal models [71, 72].

Matricaria chamomilla

An analgesic and peripheral neuropathy inhibiting function of the plant has been documented in animal models [73]. In a clinical trial on patients with OA, the plant demonstrated inhibition of pain of the knee joint with decreased disease severity in comparison with placebo [74].

Myrtus communis

Its anti-inflammatory activity in vitro is by suppressing pro-inflammatory mediators. It also demonstrates analgesic and anti-inflammatory action through suppressing MPO, TNF-α, and IL-6 activity and leukocyte migration in mice and rats [75–77].

Nigella sativa

The seeds show anti-inflammatory and analgesic properties in vivo [78]. In a clinical study of patients with rheumatoid arthritis, the seed oil showed significant improvement of disease activity score, number of swollen joints, and duration of morning stiffness [79].

Phyllanthus emblica

The fruits exhibit suppressing action on animal inflammation [80]. In addition, P. amarus shows an anti-inflammatory effect by diminishing various pro-inflammatory cytokines [81]. It also inhibits allodynia and neuropathic pain with a decrease in MPO levels [82].

Pistacia lentiscus and P. atlantica

P. integerrima shows analgesic activity in animals [83].The anti-inflammatory action of P. lentiscus is through the reduction in TNF-α and IL-6 production and leukocyte migration into inflamed tissue [84]. Moreover, P. terebinthus shows anti-inflammatory action by decreasing LT-B4 production; masticadienonic acid, masticadienolic acid, and morolic acid are the active phytochemical agents [85].

Ruta graveolens

Its anti-inflammatory activity is by the suppression of NO, iNOS, and COX-2; rutin is the active chemical agent [86]. Ratheesh et al. reported that the plant has beneficial activity on arthritis and edema via suppressing COX-2,5-LOX and MPO, elevating antioxidant performance; polyphenolic and alkaloid fractions are the main phytochemicals [87, 88].

Sambucus ebulus

Roots show anti-inflammatory activity in rats. In addition, rhizomes may have an analgesic potential in an animal model [89].

Zingiber spp

Z. zerumbet demonstrates an anti-inflammatory action by suppressing COX-2, iNOS, NO, and PGE2 in vitro, and in animal models, Zerumbone, 3-O-methyl kaempferol, kaempferol-3-O-(2,4-di-O-acetyl-α-l-rhamnopyranoside), and kaempferol-3-O-(3,4-di-O-acetyl-α-l-rhamnopyranoside) are the main phytoconstituents [90]. Khalid et al. reported an analgesic effect of Z. zerumbet by suppressing protein kinase C and the glutamatergic system in animals [91]. Moreover, efficacy of Z. officinale in the management of OA in human has been confirmed. Daily intake of capsules of Z. officinale extract in patients did not resulted in severe toxicity, and the only adverse event was commonly mild gastrointestinal disorders [97, 98].

Conclusions

Osteoarthritis, the most common musculoskeletal disorder, torments millions of people all over the world, resulting in chronic pain, along with a reduced quality of life, accompanied by elevated health costs. Presently, there is no effective treatment for OA, much less a cure. Currently, we mainly aim at alleviating symptoms [92]. Research has demonstrated that glucosamine and chondroitin sulfate can stimulate proteoglycan synthesis and inhibit proteolytic enzymes, so decrease cartilage lesion. However, in a large study, there was no difference between them and placebo in alleviating pain and functional improvement [4]. There is a lot of ongoing research to investigate newer therapies for OA, including the exploration of medicinal plants in an effort to isolate possible active ingredients that may have anti-arthritic properties. Herbal medicaments are much less expensive, may be more tolerable and widely available, having hopefully fewer side effects as compared to synthetic prescription drugs [27]. A wide range of herbal medicines have been traditionally used for the management of OA. Some scientific evidence suggests that natural medicaments may benefit the management of OA. Their anti-osteoarthritic effects seem to be mediated by the suppression of oxidative stress (i.e., iNOS, NO); cartilage degradation by destructive metalloproteinases (e.g., MMP-3, MMP-9); the downregulation of inflammatory cytokines such as IL-12, IL-2, IL-8, TNF-α, IL-1α, IL-6, IL-8, IFN-γ, and NF-κB; and their antioxidant (e.g., catalase, SOD, and GPx), analgesic, and anti-nociceptive properties. Figure 1 illustrates the possible biochemical mechanisms of medicinal plants and their phytochemicals. Various in vitro and in vivo research studies support the efficacy of these natural products on OA. Nevertheless, only 5 clinical trials have been performed for the evaluation of the effectiveness, including a trial on B. serrata, another on M. chamomilla, two trials on Z. officinale, and the last one using N. sativa (Table 4). A 8-week randomized double-blind placebo-controlled trial on 30 patients with OA of the knee revealed beneficial effect of B. serrata oleo-gum resin by reduction in knee pain and frequency of the knee joint swelling along with improvement of knee flexion and walking distance significantly in comparison with placebo group (P < 0.001) [47]. In a 6-week placebo-controlled double-blind crossover trial on 30 women and 12 men with OA of the knee reported by Soltanian et al. [74], M. chamomilla ointment demonstrated amelioration of pain of knee joint in primary knee OA patient as well as alleviation of the severity of disease-associated pain significantly in comparison with placebo (P < 0.05). One-month intake of capsules containing N. sativa seeds oil in a placebo-controlled trial on 40 women with rheumatoid arthritis resulted in amelioration of disease activity score, number of swollen joints, and duration of morning stiffness significantly [79]. Two clinical studies evaluated the efficacy and safety of ginger capsules in patients with OA. In a 6-week randomized, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in 261 patients with OA of knee joint, daily intake of ginger extract capsule exhibited alleviation of pain of knee joint on standing and pain of knee after walking 50 feet significantly (P = 0.048 and P = 0.016, respectively).Ginger capsules also reduced Western Ontario and McMaster Universities OA composite indexes [97]. In a randomized controlled, double-blind, double-dummy, crossover clinical trial on 60 patients with OA of the knee, daily intake of capsules containing ginger extract (170 mg/day) for 3 weeks showed that the efficacy of ginger group was better than placebo in terms of visual analogue scale of pain and the Lequesne index, significantly (P < 0.00001 and P < 0.00005, respectively). Although in the crossover study in terms of Siegel–Castellan test, there was no significant difference between ginger extract and placebo. Result obtained from this clinical study showed that the efficacy of ginger extract in all of the evaluation was lower than the standard drug ibuprofen [98].

Fig. 1
figure 1

Possible biochemical pathways and mechanisms in the pathogenesis of OA where medicinal plants can have an effect

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Table 4 Clinical studies of medicinal plants used for the treatment for OA
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Among the clinical trials, no severe adverse effects were observed and the herbal preparations were commonly safe in human. Considering low number of human studies and their different restrictions like low methodological quality, small volume of patients, and single-center study, the levels of evidence for current review are low. Further clinical trials with high methodological quality and greater number of patients are needed to achieve more conclusive results on the potential efficacy and safety of medicinal herbs and their phytochemical agents in the management of OA.

Various natural components from medicinal plants have been isolated including dicaffeoylquinic acids, surinamensinols and acoramol, allyl amino acid derivatives and allyl sulfides, allivictoside, glucosyl kaempferol, 12-ursene 2-diketone, boswellic acid derivatives, cinnamic derivative, guggulsterol, diarylheptanoids, pseudohypericin, amentoflavone, myrtucommulones, zerumbone, kaempferol derivatives, stigmasterol and β-sitosterol, P-hydroxy benzoic acid, 5-(hydroxymethyl) furfural, bis(5-formylfurfuryl) ether, daucosterol, α-D-fructofuranosides methyl, uracil and stachydrine, procyanidine, 2-methoxy-8,12-epoxygermacra-1 7,11-trine-6-one, 2-methoxy-5-acetoxy-furanogermacr-1 en-6-one, myrrhone, sandaracopimaric acid, abietic acid, dehydroabietic acid, mansumbinone, furanodiene and furanodienone, hyperoside, isoquercitrin and hypericin, α-linolenic acid, masticadienonic acid, masticadienolic acid and morolic acid, zerumbone, 3-O-methyl kaempferol, kaempferol-3-O-(2, 4-di-O-acetyl-α-l-rhamnopyranoside) and kaempferol-3-O-(3,4-di-O-acetyl-α-l-rhamnopyranoside), and some other phenolic compounds. Tables 2 and 3 show these phytochemical agents in detail. These components can be considered as novel natural drugs that may prove useful in the management of OA. More research is needed to develop therapeutic agents with disease-modifying properties to treat OA Table 4.