Background: Osteoarthritis (OA), as one of the chronic debilitating conditions, affects 15% of people globally and is linked with serious problems, such as cardiovascular diseases, metabolic syndrome, and autoimmune inflammatory disorders. The current therapeutic options for this disease include nonsteroidal anti-inflammatory drugs, surgery, gene therapy, intrasynovial gel injection, and warm needle penetration. However, these approaches may be accompanied by considerable side effects, high costs, and some limitations for patients. Thus, using an alternative way is needed. Summary: Presently, natural compounds based-therapies, like flavonoids, have acquired much attention in the current era. One of the compounds belonging to the flavonoid family is quercetin, and its therapeutic effects on disorders related to joints and cartilage have been addressed in vivo and in vitro studies. Key Messages: In this review, we summarized evidence indicating its curative capacity against OA with a mechanistic insight.

© 2022 S. Karger AG, Basel

Introduction

Osteoarthritis (OA) is characterized as a chronic inflammatory arthritis disease whose incidence rate is 15% around the world [1, 2]. This disease is mainly accompanied by continuous degradation of the articular cartilage following episodes of bone remodeling and synovitis [3]. OA can be associated with several serious disorders, such as cardiovascular diseases [4], metabolic syndrome [5], type 2 diabetes [6], and gout [7]. The risk of this chronic ailment can be increased through some factors, such as older age, female sex, corpulence, joint injury, bone morphology, and family history [8]. Also, the role of genetic factors, such as mutations in collagen-coding genes II, IV, V, and VI, have been determined in disease progression [9]. Regarding the etiology of OA, it is stated that some inflammatory markers, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), have a pivotal role [10]. For example, TNF-α exacerbates inflammation, stimulates preosteoclast differentiation, and potentiates osteoclast survival [11]. IL-1β changes chondrocyte homeostatic stability by elevating reactive oxygen species formation, inhibiting anabolic function, and inducing articular cartilage breakdown [12]. Generally, OA patients suffer from periodic arthralgia (joint pain), stiffness, and locomotor restriction symptoms [13, 14]. Among these, the substantial problem for the majority of patients is related to pain [15]. Therefore, the main purpose of current therapeutic methods is pain relief. In this line, the most used drugs by the patients are nonsteroidal anti-inflammatory drugs, which can relieve joint pain [16]. Other therapeutic options include surgery, intrasynovial gel injection, gene therapy, and warm needle penetration; however, some limitations have been mentioned for some of these approaches, like notable side effects, high costs, and limited use for patients [16-20]. Thus, finding an affordable and efficient approach with the minimum side effects is suggested [21]. These days, natural remedies, which are generally known as less harmful treatments, have gained much attention among different populations for the management of different problems and general health improvement [22, 23]. In this regard, several pharmacological effects have been mentioned for flavonoids, as popular natural compounds present in fruits and vegetables, such as anti-inflammatory, antioxidative, and anticancer features [24-28]. One of the flavonoids effective in treating arthritic disorders, like OA, is quercetin (Que), which is in the spotlight owing to its therapeutic effects [29, 30]. For these reasons, we aimed to review and summarize the therapeutic potential of Que against OA with a mechanistic insight.

OA and Its Pathogenesis

The pathogenesis of OA is multifactorial and has not been completely understood yet [31]. However, it has been demonstrated that different cells are involved in disease pathogenesis, like osteocytes, chondrocytes, subchondral bone osteoblasts, mononuclear cells existing in the synovial membrane, and synovial lining cells [32]. Moreover, the role of some agents in the pathogenic processes of the disease has been demonstrated, such as mechanical pressure, activated proinflammatory mediators, cell senescence, and genetic alterations [33-35]. These pathologic agents target the articular cartilage, which in normal situations comprises extracellular matrix (ECM), including chiefly chondrocytes, proteoglycans (mainly aggrecan), and collagen type II, IX, and XI [32]. Mechanical pressure (mechanical load) can trigger a signaling pathway that can eventually lead to degenerative lesions of articular cartilages [36]. This signaling has been clarified by two main pathways: (A) a pathway related to the release of growth factors from the ECM, which stimulates tissue repair and (B) a pathway controlling inflammatory signaling and is called mechanoflammation [37]. The upstream pathways of mechanoflammation can result in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) that control the regulation of nerve growth factor, the main mediator of pain in humans [37-40]. NF-κB and MAPK signaling are vital for the stimulation of different inflammation-associated cytokines [41, 42]. Proinflammatory cytokines, like IL-1, can stimulate some matrix metalloproteinases (MMPs) in vitro and inhibit the production of proteoglycan [43]. IL-6, IL-15, TNF-α, IL-17, and IL-18 are other inflammatory cytokines involved in the pathogenesis of OA probably by elevating the production of MMPs related-enzymes and reducing the formation of collagen type II [44-46]. Another factor effective in OA occurrence is chondrocyte senescence which occurs with aging. Senescence means the arrest of cell proliferation in a steady state due to stressing the cellular environment [47]. Senescent cells secrete a factor named the senescence-associated secretory phenotype. This factor can alter the microenvironment of the stressed tissue by secreting various extracellular modulators, such as proteases, cytokines, chemokines, growth factors, and bioactive lipids [48, 49]. In the joint tissue, chondrocyte senescence-associated secretory phenotype is capable of production of matrix-degrading proteases, such as MMP-1 and -13 [50]. The targets of these enzymes are aggrecan and collagens in the cartilage environment, which naturally helps the maintenance and stability of the articular cartilage [32]. Articular cartilages may be susceptible to degeneration in light of potential genetic malformations [8]. In this direction, the +104T/C polymorphism in growth differentiation factor 5 (GDF5) has been linked with the etiology of knee OA [51]. GDF5 is one of the earliest genes related to the embryonic joint interzone and participates in the formation of joint tissues, like ligaments, menisci, synovium, and articular cartilage [52]. The mutations in the GDF5 gene lead to epiphyseal dysplasia, one of the landmarks of hip OA [53, 54]. Also, both overexpression and downregulation of this gene are thought to be associated with OA [55, 56]. Its overexpression results in a failure in joint formation, hypertrophy of skeletal elements, and excessive proliferation of epiphyseal cartilage [8, 57, 58]. On the other hand, decreased GDF5 expression is linked with the degradation of chondrocyte ECM [59]. Other findings have shown that genes related to GDF5, such as OPG, RANKL, and collagen type II genes, are involved in this pathologic condition (Fig. 1). These genes cause irregular bone remodeling and decreased mineralization in an abnormal state [60].

Fig. 1.

OA and its pathogenic mechanisms. IL, interleukin; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNF-α, tumor necrosis factor-α; MMPs, matrix metalloproteinases; NGF, nerve growth factor; GDF5, growth differentiation factor 5; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor kappa-B ligand; SASP, senescence-associated secretory phenotype.

Que: Therapeutic Benefits and Challenges

Que, as one of the six subclasses of flavonoid compounds, and its derivations are used in many industries, such as the medical and food industries [61]. In medical industries, Que can exert health-promoting effects in different human and animal cellular models because of its antioxidant and anti-inflammatory [61], antimicrobial [62], anticancer [63], wound healing [64], antiallergic [65], and antidiabetic effects [66]. Furthermore, Que can be a suitable candidate to fight against viral agents like severe acute respiratory syndrome coronavirus 2 [67], cardiovascular diseases [68], and autoimmune disorders [69]. In addition, the anti-Alzheimer’s features of Que have been approved by inhibiting tau phosphorylation and amyloid-β aggregation [70]. Despite these, using Que has some pharmacological limitations, for example, very low solubility in water and high instability in the heat, light, and air [71]. Also, Que bioavailability, defined as the first administered dose that reaches the systemic circulation, is minimum because of its mass metabolism; thereby, its high dosage administration is needed [61]. Fortunately, modification processes can improve these problems [72]. These processes are divided into two types; either a derivation of Que or recombination with other active groups. The first type alters the structure of Que and enhances its solubility through derivation, whereas the second exerts a synergistic effect with the help of active groups, for instance, metal ions and complex ions; thus, the pharmacological action and bioactivity of Que can considerably be improved [72]. As a result, it seems that Que is a potential option for many medical purposes, and its curative influences can be increased by using the strategies that improve its bioavailability and solubility properties.

Que and OA

Many in vitro and in vivo studies have focused on the therapeutic effects of Que on joint related-disorders, especially OA [73-75]. In preclinical studies of OA, rheumatoid arthritis (RA), and gouty arthritis, Que has revealed significant antiarthritic properties and joint protective effects [73]. This natural compound has protective impacts on articular cartilage by interfering with the p38 MAPK pathway [76]. MAPK is a signaling protein related to OA that has a critical role in monitoring the function of pathways modulating the formation and activity of factors of joint tissue damage [76, 77]. Que can also be effective in OA prevention and treatment by regulating the expression of inflammatory factors by blocking the p38 MAPK signaling pathway [78]. In an experimental work, the importance of suppression of inflammatory mediators in OA amelioration was highlighted. In detail, this work showed that Que reduced OA progression likely due to IL-1β and TNF-α inhibition via the TLR-4/NF-κB pathway [79]. Similarly, Li et al. [30] assessed the antiarthritic capacity of Que through its intraperitoneal injection into OA model rats. They found that Que suppressed inflammation stimulated by IL-1β and cartilage degradation by curbing the IRAK1/NLRP3 pathway [30]. Moreover, another study investigated the immunomodulatory impact of Que on OA in vivo and in vitro, and it was concluded that Que makes a pro-chondrogenic circumstance and potentiates cartilage repair through the regulation of polarization of synovial macrophages to M2 macrophages [74]. Also, an investigation in 2019 studied the effects of Que in animal models of surgical-induced OA. In this work, Que upregulated tissue inhibitor of metalloproteinases-1 and superoxide dismutase expressions, attenuated MMP-13 expression, and improved OA degeneration by decreasing oxidative stress and curbing the degradation of ECM of the cartilage [80]. Other therapeutic mechanisms of Que against OA can include suppression of macrophage and neutrophil recruitment, proteoglycan degradation, cytokine production, like IL-6 and IL-10, and Nrf2/HO-1 pathway activation, bone resorption, as well as the COX-2 mRNA expression (Fig. 2) [81]. In Table 1, therapeutic capacity of Que in treating OA has been summarized. On the whole, it seems that Que can be a desired candidate for OA treatment through various mechanisms, like improving the antioxidant system, regulating immune system reactions, and affecting signaling pathways related to joint and cartilage repair.

Table 1.

Reports regarding curative impacts of Que in treating OA have been summarized with a focus on its effects/mechanism against the disease

Fig. 2.

Que and its biologic and pharmacologic mechanisms for OA treatment. SOD, superoxide dismutase; ECM, extracellular matrix; TLR-4, Toll-like receptor 4; IRAK1, interleukin-1 receptor associated kinase 1; NLRP3, NLR family pyrin domain containing 3; Nrf2, nuclear factor erythroid 2-related factor; HO-1, heme oxygenase-1; COX-2, cyclooxygenase-2.

Que and Clinical Trials

Many clinical trials have been carried out to evaluate Que effects on many systematic and regional disorders, like RA [82], OA [83], and many other diseases [84-87]. For example, Kanzaki et al. [83] scrutinized the effect of the administration of a supplement containing Que glycosides, chondroitin sulfate, and glucosamine hydrochloride on 40 Japanese persons with knee OA. This project implicated that this supplement could improve symptoms related to OA according to the Japanese Orthopedic Association criteria [83]. In another clinical work, a supplement containing Que glucoside, chondroitin, and glucosamine, was prescribed orally in patients with OA and RA. This study demonstrated that the supplement could dramatically ameliorate pain symptoms, visual analog scale, and daily activities in OA cases. However, these impacts were not found in RA cases. In addition, they observed a remark reduction in the level of chondroitin 4-sulfate, which is formed through injured articular cartilage [88]. Javadi et al. [82], in a randomized controlled trial, studied the influence of Que on clinical symptoms, disease severity, and inflammation in RA patients. Based on this research, Que consumption for 8 weeks diminishes early morning stiffness and pain considerably. Plus, the high-sensitivity TNF-α plasma level was remarkably reduced [82]. However, one clinical study showed that Que had no impact on blood pressure and inflammatory and oxidative situation of RA subjects [89]. It looks like the curative influences of Que need to be more evaluated in clinical studies.

Conclusion

OA, as one of the debilitating diseases, involves a great number of subjects worldwide and is linked with serious conditions that may be threatening life, like cardiovascular diseases, metabolic syndrome, and autoimmune diseases. Among this, treatment with natural supplements, especially Que, has gained considerable attention due to its fewer side effects and high effectiveness. It has been indicated that Que can be a novel candidate against OA through various mechanisms, like modification of inflammatory agents, such as IL-1β, TNF-α, IL-6, and IL-10, inhibition of oxidative stress, ECM degeneration of the cartilage, and decrease of chondroitin 4-sulfate level; however, more experimental and clinical investigations are demanded to approve its effectiveness for OA treatment.

Acknowledgments

The figures were created by the web-based software BioRender.

Conflict of Interest Statement

The authors declare no conflict of interest.

Funding Sources

This work was not financially supported.

Author Contributions

Faezeh Samadi contributed to the write-up of the review article. Mohammad Saeed Kahrizi, Fateme Heydari, Hossein Roghani-Shahraki, Abnoos Mokhtari Ardekani, and Fatemeh Rezaei-Tazangi designed the framework of the manuscript. Reza ArefNezhad contributed to the acquisition, analysis, and interpretation of data for the work.

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