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 [ ].

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 [ ]. 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, TNF-α, IL, and IL 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 [ ]. 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 [ 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].

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. These genes cause irregular bone remodeling and decreased mineralization in an abnormal state [ 60 ].

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, 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 ]. 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. Many in vitro and in vivo studies have focused on the therapeutic effects of Que on joint related-disorders, especially OA [ ].

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. Similarly, Li et al. 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 M 2 macrophages [ 74 ].

Also, an investigation in 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 expression, and improved OA degeneration by decreasing oxidative stress and curbing the degradation of ECM of the cartilage [ 80 ].

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.

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 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 [ ].

For example, Kanzaki et al. 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. 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. 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, 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.

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. Sign In or Create an Account.

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OA and Its Pathogenesis. Que: Therapeutic Benefits and Challenges. Que and OA. The quercetin paradox. Toxicol Appl Pharmacol. Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP. Oxidative damage and protection of the RPE. Prog Retin Eye Res.

Chan MM, Mattiacci JA, Hwang HS, Shah A, Fong D. Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. Bio Pharm.

Chuang CC, Martinez K, Xie G, et al. Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-{alpha}-mediated inflammation and insulin resistance in primary human adipocytes.

Am J Clin Nutr. Dajas F. Life or death: neuroprotective and anticancer effects of quercetin. J Ethnopharmacol. Dower JI, Geleijnse JM, Gijsbers L, Zock PL, Kromhout D, Hollman PC. Effects of the pure flavonoids epicatechin and quercetin on vascular function and cariometabolic health: a randomized, double-blind, placebo-controlled, crossover trial.

Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetin reduces blood pressure in hypertensive subjects.

J Nutr. Egert S, Bosy-Westphal A, Seiberl J, et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a doule-blinded, placebo-controlled cross-over study.

Br J Nutr. Gates MA, Tworoger SS, Hecht JL, De Vivo I, Rosner B, Hankinson SE. A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer. Int J Cancer. Giuliani C, Noguchi Y, Harii N, Napolitano G, Tatone D, Bucci I, Piantelli M, Monaco F, Kohn LD.

The flavonoid quercetin regulates growth and gene expression in rat FRTL-5 thyroid cells. Guardia T, Rotelli AE, Juarez AO, Pelzer LE. Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin, and hesperidin on adjuvant arthritis in rat. Hanninen, Kaartinen K, Rauma AL, Nenonen M, Torronen R, Hakkinen AS, Adlercreutz H, Laakso J.

Antioxidants in vegan diet and rheumatic disorders. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. Food Chem Toxicol. Kleemann R, Verschuren L, Morrison M, et al.

Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, Hakkinen S et al. Quercetin intake and the incidence of cerebrovascular disease.

Eur J Clin Nut. Kurowska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, Piche LA, Serratore P. HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Lam TK, Rotunno M, Lubin JH, et al. Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue and lung cancer risk.

Lamson DW, Brignall MS. Antioxidants and cancer III: quercetin. Alt Med Rev. Li N, Sun C, Zhou B, et al. Low concentration of quercetin antagonizeds the cytotoxic effects of anti-neoplastic drugs in ovarian cancer.

PLoS One. Longanga OA, Vercruysse A, Foriers A. Contribution to the ethnobotanical, phytochemical and pharmacological studies of traditionally used medicinal plants in the treatment of dysentery and diarrhoea in Lomela area, Democratic Republic of Congo DRC.

Mackraj I, Govender T, Ramesar S. The antihypertensive effects of quercetin in a salt-sensitive model of hypertension. J Cardiovasc Pharmacol. Maso V, Calgarotto AK, Franchi GC, et al. Multitarget effects of quercetin in leukemia.

Cancer Prev Res Phila. Otshudi AL, Foriers A, Vercruysse A, Van Zeebroeck A, Lauwers S. In vitro antimicorbial activity of six medicinal plants traditionally used for the treatment of dysentery and diarrhoea in Democratic Republic of Congo DRC. J Am Coll Nutr ; 36 1 : 9- Gokhale JP, Mahajan HS, Surana SJ.

Quercetin loaded nanoemulsion-based gel for rheumatoid arthritis: In vivo and in vitro studies. Biomed Pharmacother ; 7 : Available from:. Ansari MM. Neha, Khan HA. Quercetin alleviate oxidative stress and inflammation through upregulation of antioxidant machinery and down-regulation of COX2 and NF-κB expression in collagen induced rheumatoid arthritis.

Int J Drug Dev Res ; 6 1 : Yuan K, Zhu Q, Lu Q, et al. Quercetin alleviates rheumatoid arthritis by inhibiting neutrophil inflammatory activities. Zhang J, Yin J, Zhao D, et al. Therapeutic effect and mechanism of action of quercetin in a rat model of osteoarthritis.

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Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. Boots AW, Li H, Schins RP, Duffin R, Heemskerk JW, Bast A, Haenen GR. The quercetin paradox. Toxicol Appl Pharmacol.

Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP. Oxidative damage and protection of the RPE. Prog Retin Eye Res. Chan MM, Mattiacci JA, Hwang HS, Shah A, Fong D. Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway.

Bio Pharm. Chuang CC, Martinez K, Xie G, et al. Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-{alpha}-mediated inflammation and insulin resistance in primary human adipocytes.

Am J Clin Nutr. Dajas F. Life or death: neuroprotective and anticancer effects of quercetin. J Ethnopharmacol. Dower JI, Geleijnse JM, Gijsbers L, Zock PL, Kromhout D, Hollman PC.

Effects of the pure flavonoids epicatechin and quercetin on vascular function and cariometabolic health: a randomized, double-blind, placebo-controlled, crossover trial. Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetin reduces blood pressure in hypertensive subjects.

J Nutr. Egert S, Bosy-Westphal A, Seiberl J, et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a doule-blinded, placebo-controlled cross-over study.

Br J Nutr. Gates MA, Tworoger SS, Hecht JL, De Vivo I, Rosner B, Hankinson SE. A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer. Int J Cancer. Giuliani C, Noguchi Y, Harii N, Napolitano G, Tatone D, Bucci I, Piantelli M, Monaco F, Kohn LD.

The flavonoid quercetin regulates growth and gene expression in rat FRTL-5 thyroid cells. Guardia T, Rotelli AE, Juarez AO, Pelzer LE. Anti-inflammatory properties of plant flavonoids.

Effects of rutin, quercetin, and hesperidin on adjuvant arthritis in rat. Hanninen, Kaartinen K, Rauma AL, Nenonen M, Torronen R, Hakkinen AS, Adlercreutz H, Laakso J. Antioxidants in vegan diet and rheumatic disorders. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC.

Food Chem Toxicol. Kleemann R, Verschuren L, Morrison M, et al. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, Hakkinen S et al.

Quercetin intake and the incidence of cerebrovascular disease. Eur J Clin Nut. Kurowska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, Piche LA, Serratore P. HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Lam TK, Rotunno M, Lubin JH, et al. Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue and lung cancer risk.

Lamson DW, Brignall MS. Antioxidants and cancer III: quercetin. Alt Med Rev. Li N, Sun C, Zhou B, et al. Low concentration of quercetin antagonizeds the cytotoxic effects of anti-neoplastic drugs in ovarian cancer.

PLoS One. Longanga OA, Vercruysse A, Foriers A. Contribution to the ethnobotanical, phytochemical and pharmacological studies of traditionally used medicinal plants in the treatment of dysentery and diarrhoea in Lomela area, Democratic Republic of Congo DRC.

Mackraj I, Govender T, Ramesar S. The antihypertensive effects of quercetin in a salt-sensitive model of hypertension. J Cardiovasc Pharmacol. Maso V, Calgarotto AK, Franchi GC, et al.

Multitarget effects of quercetin in leukemia. Cancer Prev Res Phila. Otshudi AL, Foriers A, Vercruysse A, Van Zeebroeck A, Lauwers S.

In vitro antimicorbial activity of six medicinal plants traditionally used for the treatment of dysentery and diarrhoea in Democratic Republic of Congo DRC. Owen RW, Giacosa A, Hull WE, Haubner R, Spiegelhalder B, Bartsch H. Eur J Cancer. Owen RW, Mier W, Giacosa A, Hull WE, Spiegelhalder B, Bartsch H.

Identification of lignans as major components in the phenolic fraction of olive oil. Clin Chem. Ramos S. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J Nutr Biochem. Epub Feb Ruiz PA, Braune A, Holzlwimmer G, Quintanilla-Fend L, Haller D.

Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. Shoskes D, Nickel J. Urologic Clinics of North America. Saunders Company. Staedler D, Idrizi E, Kenzaoui BH, Juillerat-Jeanneret L.

Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells. Cancer Chemother Pharmacol. Taepongsorat L, Tangpraprutgul P, Kitana N, Malaivijitnond S. Stimulating effects of quercetin on sperm quality and reproductive organs in adult male rats.

Asian J Androl. Thornhill SM, Kelly AM. Natural treatment of perennial allergic rhinitis. Wang P, Zhang K, Zhang Q, et al. Effects of quercetin on the apoptosis of the human gastric carcinoma cells.

Toxicol in Vitro.