Unraveling Natural Products' Role in Osteoarthritis Management-An Overview.

The natural process of aging gradually causes changes in living organisms, leading to the deterioration of organs, tissues, and cells. In the case of osteoarthritis (OA), the degradation of cartilage is a result of both mechanical stress and biochemical factors. Natural products have already been evaluated for their potential role in the prevention and treatment of OA, providing a safe and effective adjunctive therapeutic approach. This review aimed to assess the therapeutic potential of natural products and their derivatives in osteoarthritis via a systematic search of literature after 2008, including in vitro, in vivo, ex vivo, and animal models, along with clinical trials and meta-analysis. Overall, 170 papers were obtained and screened. Here, we presented findings referring to the preventative and therapeutic potential of 17 natural products and 14 naturally occurring compounds, underlining, when available, the mechanisms implicated. The nature of OA calls to initially focus on the management of symptoms, and, in that context, several naturally occurring compounds have been utilized. Underlying a global need for more sustainable natural sources for treatment, the evidence supporting their chondroprotective potential is still building up. However, arriving at that kind of solution requires more clinical research, targeting the implications of long-term treatment, adverse effects, and epigenetic implications.


Introduction
In the words of the writer Janne Teller: "From the moment we are born, we begin to die."; aging poses a natural, inevitable, and irreversible process. Even in a healthy organism, aging affects a broad spectrum of functioning aspects on physiological, cellular, and tissue level, which are subject to deterioration due to exposure to a series of environmental factors [1]. At a molecular level, this decline is characterized by the increasing accumulation of molecular damage due to free radicals environmentally and metabolically generated, errors and malfunctions in biochemical reactions caused without premeditation or external stimulus, and nutritional components. Changes in the synthesis and arrangement of key proteins, such as collagen, as well as proteoglycans over time, are observed due to aging as the metabolism of cells in articular joint tissues in normal and pathological conditions is highly affected [2,3].
It is a common belief that some reactive oxygen species (ROS) can cause or aggravate a series of human pathologies, mostly owed to direct damage induced to sensitive and biologically significant targets. Although the ability of antioxidants in the context of prevention or treatment of oxidative

Avocado/Soybean
Avocado/soybean unsaponifiables belong in the class of symptomatic slow-acting drugs, which following published reports, have demonstrated the potential to lessen the synthesis of some mediators of osteoarthritis-related inflammation by interfering with a variety of molecules and pathways implicated and cartilage catabolism, in addition to demonstrated pain alleviation and physical function improvement [29,30]. In the context of anticatabolic features of Avocado/soybean unsaponifiables (the oily extracts that remain after soap manufacture, which include phytosterols, lipophilic vitamins, and tri-terpenoids), the administration of the extract exhibited the potential to avert cartilage degradation by suppressive means over the expression and activity of biomarkers related to non-collagenous proteins, matrix metalloproteinases (MMP-3, MMP-13), and increasing Tissue Inhibitor of Metalloproteinase (TIMP-1) [31]. Namely, the findings of animal studies conducted over the last decade indicate that intervention was able to reduce the joint edema resulting from Monosodium Iodoacetate (MIA) injection after 30 days of intervention (dose: 35 mg/day) [29,32], while, in treated dogs, researchers observed histological improvement of cartridge lesions and significant abatement in iNOS and MMP-13 levels [33]. Finally, the joint diameter was decreased in a moderate yet statistically significant way, and Hindlimb weight-bearing notably improved in the treatment group [29,32]. The finding reflects the capacity of this treatment to temper painful OA in the in vivo setting, which is also observed via clinical trials that have been discussed further in this review.

Chrysanthemum zawadskii
Chrysanthemum L. (Asteraceae-Anthemideae) is a plant variety widely found in East Asia. Published reports have documented the anti-inflammatory perspective and antioxidant capacity of the plant extract in the setting of in vitro and in vivo studies [34][35][36], with the experimental focus recently targeting the inhibitory assets on the differentiation of osteoclasts and protective activities against arthritis [37]. Evidently, pro-inflammatory biomarkers-IL-1β, IL-6, COX-2, and iNOS-were inhibited by actions of a hexane/ethanol extract (or other fragmentations) of Chrysanthemum zawadskii in RAW 264.7 cells, potentially through heme oxygenase-1 induction [38,39]. Furthermore, the ethanol extract of Chrysanthemum exhibited suppressive attributes over MMP-2 and MMP-13 levels in MIA-induced osteoarthritic rats [40]. Additionally, oral intervention with 50-200 mg/kg Chrysanthemum zawadskii was found to suppress the protein expression of pro-apoptotic molecules and to attenuate serum cartilage oligomeric matrix protein [40]. Finally, improvement in common OA symptoms of swelling and walking difficulty was also reported after oral administration to rats of different concentrations: 50, 100, and 200 mg/kg [40]. An intriguing finding from a recent study of 2016 has also highlighted the anti-adipogenic qualities of the Chrysanthemum zawadskii extract [41], studied among other herbs, providing yet another possibility of the plant within the framework of OA management and/or prevention.

Guilu Erxian Glue
There is a growing interest in an herbal mixture that originated in Chinese tradition with reported useful assets in the treatment of some conditions. In particular terms, guilu erxian (GE) glue has been under investigation for its therapeutic potential against joint pain, muscle strength, and disease progression within the context of knee OA, in addition to bone marrow injury and osteoporosis, mostly in the cellular level [42][43][44][45]. For the purposes of this review, we presented the findings of a 2018 study by Chou et al., who evaluated two formulations extracted from GE glue, namely, GE paste and GE liquid in male-induced osteoarthritic mice [44], and reports of a 2014 clinical trial in a population of elderly men with knee OA, which have been presented in the respected segment of the review [45]. In the in vivo setting of anterior cruciate ligament transection (ACLT)-induced OA, the effects of a 28-days intervention with GE in the form of either paste or liquid were evaluated in two treatment doses (100 mg/kg/day or 300 mg/kg/day) [42] against phosphate-buffered saline and celecoxib (10 mg/kg/day). Notably, the intervention with the liquid mixture formulation in the minimum dose was able to considerably lessen the mRNA levels of IL-1β, IL-6, and TNF-α, as well as the protein expression of IL-1β and TNF-α, compared to either formulation at high dose and celecoxib [44]. Both formulations presented a notable and dose-dependent reduction of osteolytic lesions, cartilage erosion, and bone spur formation in addition to reductions observed in proteoglycan, chondrocyte, and cartilage damage [44]. Although the formulations of this mixture presented chondroprotective properties with anti-inflammatory characteristics, the evidence supporting those allocations remain inconclusive.

Japanese Pepper or Korean Pepper (Zanthoxylum piperitum)
Zanthoxylum piperitum (Rutaceae family)-an aromatic spiny shrub-is commonly known as Japanese pepper or Korean pepper and has also been reported to have antibacterial, antimicrobial, and some anti-inflammatory attributes, mostly investigated in the form of essential oil [46][47][48][49].
Zanthoxylum piperitum essential oil was tested in an animal model setting. The outcomes of the 2016 study demonstrated some remarkable primary effects on the first phase of the formalin-induced licking, glutamate, and hot plate tests; however, these positive conclusions did not endure throughout the study as the oil did not affect reducing paw licking induced by capsaicin or against inflammation induced by carrageenan, as observed through further testing in the same study [50].
In a more recent in vitro study investigating Zanthoxylum piperitum ethanolic extract, the findings revealed strong inhibitory activity of the extract in the Lipopolysaccharide (LPS)-induced RAW Antioxidants 2020, 9, 348 6 of 34 264.7 cell line, as well as suppressive characteristics against reactive oxygen species production, COX-2, and iNOS. Further, in vivo analysis on the MIA-induced OA model revealed that 100 mg/kg oral-treatment significantly inhibited MIA-induced edema and articular cartilage thickness. Notably, acetic acid, heat, and formalin-induced pain were remarkably decreased by both intervention doses of the ethanolic plant extract (50 and 100 mg/kg) in a dose-dependent manner. Finally, the inflammation and pain-related effects of the intervention were also evaluated in BV-2 cells and by mouse-ear thickness and biopsy punch weight measurements [51].
According to the 2015 in vivo study, treatment with a 70% ethanolic extract of Litsea japonica fruit in MIA-induced OA rats was found to improve the bone volume and cross-section thickness, while it also curbed the expression levels of inflammatory cytokines. It must also be noted that high doses (100 mg/kg or 200 mg/kg) in the treatment groups resulted in a remarkable 80% inhibition of MMPs or MMPs tissue inhibitors threshold when compared to the respected control group [55]. Similar results were reported in the 2017 in vivo study, in which the n-hexane extract of Litsea japonica fruit flesh considerably reduced the difference in weight-bearing capabilities of the hind paws among healthy and MIA-treated rats, while cartilage and bone destruction were also hindered [56]. Additionally, this treatment actively attenuated MMP-2, MMP-9, COX-2 expression, along with serum levels of deoxypyridinoline (DPD) and osteocalcin. Moreover, this intervention considerably suppressed inflammatory cells' infiltration and attenuated TNF-α, IL-1, and IL-6 levels in joints. Accordingly, the intervention also lessened NO, PGE 2 , IL-6, and TNF-α production in LPS-activated macrophages, while serum concentrations of leukotriene B4 (LTB4) and lipoxygenase (LOX) were also essentially lowered [56]. Finally, it must be noted that, in some cases, the curative assets of the extract/or extract fractions, evaluated in RAW 264.7 cell-line, have, in fact, been owed to the single action of isolated constituents, namely, litsenolide-B 2 , which has exhibited useful properties against pro-inflammatory mediators [57].

Mistletoe Fig (Ficus deltoidea)
Ficus deltoidea Jack, commonly known as mistletoe fig, found in several parts of the globe, has been traditionally utilized in folk medicine. Several studies have determined some qualities of the plant extract, in the context of antioxidant or antimicrobial competence, while others have focused on its inhibitory assets against inflammation [59][60][61][62]. Three studies that took place over the past four years have assessed the potential of the plant in the context of experimental models [63][64][65]. Initial in vitro results of the 2016 survey investigating the impact of Ficus deltoidea (FD) leaves extract supplementation on OA through IL-1β-induced bovine cartilage explant exhibited inhibitory properties of this intervention on proteoglycan loss in addition to an increasing tendency of chondrocytes proliferation [63]. It must be noted that this research studied the supplementation with the plant extract against diclofenac, in the setting of MIA-induced OA postmenopausal rats. Data reported from this 28-days intervention in healthy or osteoarthritic rats suggested that levels of IL-1β, PGE 2 , Procollagen II N-terminal pro-peptide (PIINP), and C-telopeptide of type II collagen (CTX-II) elevated in the serum OA rats, and largely reduced after supplementation with the FD extract and the active comparator [63]. Both 2016 and 2017 studies, referring to MIA-induced OA postmenopausal rat models, demonstrated the effects of a decrease in IL-1β, PGE 2 , and C-telopeptide type II collagen levels in serum, while observations of attenuated cartilage erosion were reported in both intervention groups. However, the second (2017) research also highlighted that similarly to diclofenac, the plant extract intervention (dose equivalent of 60 mg/kg for humans) down-regulated the IL-1β, PGE 2 receptor, and MMP-1 mRNA expressions in the osteoarthritic cartilages, which seemed to be dose-dependent [64]. Finally, a study conducted in 2018 by the same team aimed to provide bases on the inconclusive osteoporosis/osteoarthritis relationship [65].
3.1.8. Pink Trumpet Tree -(Tabebuia avellanedae) Handroanthus impetiginosus or Tabebuia avellanedae or pink trumpet tree is a native Bignoniaceae tree of America; however, different varieties of the tree may have also been introduced to other locations. Several studies have documented a series of characteristics of the plant, derived from various locations (Paraguay, Brazil, India, and others), using ethanolic, methanolic, or water extracts of mostly the bark of the plant [66][67][68][69]. More commonly, the antimicrobial properties of the plant have been investigated; however, there are some reports of anti-inflammatory activity [70][71][72][73].
In an early 2008 study, evaluating the anti-inflammatory properties of the water extract of Tabebuia avellanedae in the setting of lipopolysaccharide-stimulated macrophages, results suggested that the treatment had significant inhibitory effects on PGE 2 and NO production, as well as the expression of COX-2 and iNOS, in LPS-stimulated RAW 264.7 cells [70]. Similarly, in the setting of induced edema at the mouse ear by arachidonic acid (COX-2 activator) or croton oil (LOX activator), a week's supplementation with the water extract of Tabebuia avellanedae (100 mg/kg) was able to alleviate the arachidonic acid-induced edema as opposed to the edema induced by croton oil, which was not actively affected [70]. In a similar context, the ethanolic extract (doses: 100 mg/kg or 200 mg/kg) was evaluated against pain and inflammation versus a control group [71]. The results of this study demonstrated an approximate 30% increase in pain in the treatment group at dose 200 mg/kg. The same dose was additionally able to inhibit 30%-50% of inflammation of tissue plasminogen activator (tPA)-induced paw edema, (arachidonic acid or carrageenan) compared to control [71]. Finally, it must be said that TabetriTM had also documented inhibitory effects on inflammatory mediators and proinflammatory cytokines in a dose-dependent manner. Although this product is referred to as the ethanol extract of Tabebuia avellanedae, as a commercial product, it did not fall in the scope of this review and was not further investigated [74].
As in the cases of many other plant extracts exhibiting therapeutic characteristics, it must be noted that a number of compounds isolated from the water extract of the plant, inter alia, some cyclopentenyl esters, and the known naphthoquinone: lapachol, have been documented to have in vitro anti-inflammatory properties as well [72,73,75]. Notably, some of these derivatives effectively ameliorated NO, PGE 2 , TNF-α, and IL-1β production. On that note, it is essential to highlight once more that research has yet been inconclusive on whether the plant extract characteristics are owed to some selected compounds or its combined properties.

Pomegranate (Punica granatum)
Pomegranate (Punica granatum L.) is undoubtedly one of the oldest known edible fruits of the Punicaceae family and has long been studied for its effects on a number of diseases [76][77][78]. A recent 2018 study investigated the anti-inflammatory properties of pomegranate peels in the form of their acetone extract and reported significant reductions of iNOS, COX-2, and MMP-13 in primary rat chondrocytes, as well as changes in the weight-bearing ratio in experimental OA in rats [79]. The same study has further evaluated the properties of punicalagin (Scheme 1). This ellagitannin also exhibited some chondroprotective properties after 28 days of supplementation (0.50 mg/kg), but it was not superior to the peel extract against PGE 2 production (19.1%) [79]. Almost a decade earlier, a study was also conducted in an animal model using different doses of pomegranate juice (4 mL/kg, 10 mL/kg, or 20 mL/kg) in the setting of early MIA-induced OA. As reported, although proteoglycan and cell proliferation were not actively affected, the intervention (dose-dependently) prevented the negative effects of iodoacetate, as well as chondrocyte damage [80]. In a similar way, a 2010 study investigating the potentials of a polyphenol-rich pomegranate extract in the context of IL-1β-induced human chondrocytes demonstrated that the intervention was able to actively decrease the IL-1β-induced activation of mitogen-activated protein kinase kinase-3 (MKK3), p38α-MAPK isoform, and DNA binding activity of the transcription factor Runt-related transcription factor 2 (RUNX-2) [81].

Ryupunghwan
In a recent study, Hong G.U. et al. presented the OA modulating potential of a botanical formula, which is particularly common in Korea, mostly well known as Ryupunghwan (RPH) [82]. The formula contains a number of natural products, such as Astragalus membranaceus, Turnera diffusa, Achyranthes bidentata, Angelica gigas, Eclipta prostrata, Eucommia ulmoides, and Ilex paraguariensis, most of which are traditionally used in folk medicine. The formula was tested in the context of positive properties against OA, via in vitro experiments on cellular IL-1β-stimulated chondrosarcoma, SW1353 cell model [82]. As reported in this recent work, the pre-treatment with RPH had a suppressive effect on the mediators that contributed to the progression of osteoarthritis by inhibiting collagen 2, COX-1-2, MMP-13, TNF-α, and IL-13 expression [82]. In the case of RPH formula, two components-isomucronulatol 7-O-β-d-glucoside and Ecliptasaponin A (Scheme 2)-were found to be present in higher concentration levels, and Ecliptasaponin A was further found to play a crucial role against OA, even higher than isomucronulatol 7-O-β-d-glucoside (IMG's) [82].

Sargassum serratifolium
Sargassum spp. (a brown seaweed) and plastoquinones (Scheme 3), which are present in high volumes in Sargassum serratifolium (C. Agardh), are known for several documented substantial anti-inflammatory and anti-oxidative assets [83,84]. Notably, sargachromenol, sargahydroquinoic acid, and sargaquinoic acid have been identified in a 2017 study presented by Joung E. et al. as the main components of inflammatory suppression in the ethanolic fraction of the plant, repressing NO production [85]. A recent 2018 research by Park C. et al. investigated Sargassum serratifolium extract (EtOH 70%) in human-stimulated IL-1β chondrocyte cell line and early murine synovial cells [86]. The high antioxidant profile of the EtOH fragment was found in both cell lines. as well as active reduction of ROS, while anti-inflammatory assets were also documented as a result of the decreased expression of COX-2, iNOS, in addition to decreased PGE2 and NO production, after supplementation [86]. Additionally, this Sargassum EtOH fragment intervention down-regulated MMP-1, -3, and -13 gene expression in SW1353 IL-1β-treated chondrocytes, while the NF-κB and p38 Scheme 1. Punicalagin structure.

Ryupunghwan
In a recent study, Hong G.U. et al. presented the OA modulating potential of a botanical formula, which is particularly common in Korea, mostly well known as Ryupunghwan (RPH) [82]. The formula contains a number of natural products, such as Astragalus membranaceus, Turnera diffusa, Achyranthes bidentata, Angelica gigas, Eclipta prostrata, Eucommia ulmoides, and Ilex paraguariensis, most of which are traditionally used in folk medicine. The formula was tested in the context of positive properties against OA, via in vitro experiments on cellular IL-1β-stimulated chondrosarcoma, SW1353 cell model [82]. As reported in this recent work, the pre-treatment with RPH had a suppressive effect on the mediators that contributed to the progression of osteoarthritis by inhibiting collagen 2, COX-1-2, MMP-13, TNF-α, and IL-13 expression [82]. In the case of RPH formula, two components-isomucronulatol 7-O-β-d-glucoside and Ecliptasaponin A (Scheme 2)-were found to be present in higher concentration levels, and Ecliptasaponin A was further found to play a crucial role against OA, even higher than isomucronulatol 7-O-β-d-glucoside (IMG's) [82].

Ryupunghwan
In a recent study, Hong G.U. et al. presented the OA modulating potential of a botanical formula, which is particularly common in Korea, mostly well known as Ryupunghwan (RPH) [82]. The formula contains a number of natural products, such as Astragalus membranaceus, Turnera diffusa, Achyranthes bidentata, Angelica gigas, Eclipta prostrata, Eucommia ulmoides, and Ilex paraguariensis, most of which are traditionally used in folk medicine. The formula was tested in the context of positive properties against OA, via in vitro experiments on cellular IL-1β-stimulated chondrosarcoma, SW1353 cell model [82]. As reported in this recent work, the pre-treatment with RPH had a suppressive effect on the mediators that contributed to the progression of osteoarthritis by inhibiting collagen 2, COX-1-2, MMP-13, TNF-α, and IL-13 expression [82]. In the case of RPH formula, two components-isomucronulatol 7-O-β-d-glucoside and Ecliptasaponin A (Scheme 2)-were found to be present in higher concentration levels, and Ecliptasaponin A was further found to play a crucial role against OA, even higher than isomucronulatol 7-O-β-d-glucoside (IMG's) [82].

Scheme 2. Structures of isomucronulatol 7-O-β-d-glucoside (1) and Ecliptasaponin A (2).
3.1.11. Sargassum serratifolium Sargassum spp. (a brown seaweed) and plastoquinones (Scheme 3), which are present in high volumes in Sargassum serratifolium (C. Agardh), are known for several documented substantial anti-inflammatory and anti-oxidative assets [83,84]. Notably, sargachromenol, sargahydroquinoic acid, and sargaquinoic acid have been identified in a 2017 study presented by Joung E. et al. as the main components of inflammatory suppression in the ethanolic fraction of the plant, repressing NO production [85]. A recent 2018 research by Park C. et al. investigated Sargassum serratifolium extract (EtOH 70%) in human-stimulated IL-1β chondrocyte cell line and early murine synovial cells [86]. The high antioxidant profile of the EtOH fragment was found in both cell lines. as well as active reduction of ROS, while anti-inflammatory assets were also documented as a result of the decreased expression of COX-2, iNOS, in addition to decreased PGE2 and NO production, after supplementation [86]. Additionally, this Sargassum EtOH fragment intervention down-regulated MMP-1, -3, and -13 gene expression in SW1353 IL-1β-treated chondrocytes, while the NF-κB and p38 MAPK kinase activities were also affected [86]. It is worth noting that similar results were reported

Sargassum serratifolium
Sargassum spp. (a brown seaweed) and plastoquinones (Scheme 3), which are present in high volumes in Sargassum serratifolium (C. Agardh), are known for several documented substantial anti-inflammatory and anti-oxidative assets [83,84]. Notably, sargachromenol, sargahydroquinoic acid, and sargaquinoic acid have been identified in a 2017 study presented by Joung E. et al. as the main components of inflammatory suppression in the ethanolic fraction of the plant, repressing NO production [85]. A recent 2018 research by Park C. et al. investigated Sargassum serratifolium extract (EtOH 70%) in human-stimulated IL-1β chondrocyte cell line and early murine synovial cells [86]. The high antioxidant profile of the EtOH fragment was found in both cell lines. as well as active reduction of ROS, while anti-inflammatory assets were also documented as a result of the decreased expression of COX-2, iNOS, in addition to decreased PGE 2 and NO production, after supplementation [86]. Additionally, this Sargassum EtOH fragment intervention down-regulated MMP-1, -3, and -13 gene expression in SW1353 IL-1β-treated chondrocytes, while the NF-κB and p38 MAPK kinase activities were also affected [86]. It is worth noting that similar results were reported by Joung E. et al. in a cellular setting on pro-inflammatory cytokines in mouse serum [85].

Schisandrae Fructus (Schisandra chinensis (Turcz.) Baill)
Schisandrae Fructus (SF), the dried fruit of Schisandra chinensis (Turcz.) Baill. (Magnoliaceae), is another natural product, traditionally known in the Chinese culture, but also popular in the Russian culture, yet widely used as a folk remedy for the prevention and management of several chronic inflammatory diseases [87]. SF extract in the setting of IL-1β-stimulated SW1353 chondrocytes actively attenuated IL-1β-induced expression of matrix MMP-1, -3, and -13, while the intervention also reduced the elevated levels of COX-2 and iNOS associated with PGE2 and NO production [88]. In addition, a 2015 study showed that SF markedly suppressed the nuclear translocation of NF-κB by blocking inhibitor κB-alpha degradation and exhibited repressive properties of c-Jun N-terminal kinase and p38 MAPK phosphorylation [88].

Pure Natural Compounds
Over the last decade, numerous compounds isolated from natural products have been investigated in the context of inhibiting inflammation in osteoarthritis. Here, we presented a summary of these findings, mostly based on research conducted in chondrocytes and some OA animal models. Among others, compounds like curcumin, also known as turmeric, with well-documented effects against some conditions, including arthritis [89][90][91]; thymoquinone, a compound isolated from fennel flower (Nigella sativa); representatives of flavonoids (anthocyanins (malvinidin), flavones (chrysin), and flavonols (astragalin and isorhamnetin); geniposide, an iridoid glycoside, with some affiliations against a variety of chronic inflammatory conditions [92,93]; the secoiridoid glycoside oleuropein; the well-known bioactive compound resveratrol, with many biological properties [94] and specific inhibitory properties of NF-kB, as well as COX-2 gene expression and enzyme activity [95], and the equally known rosmarinic acid with also numerous therapeutic assets [96] are included in this review. The chemical structures of all the compounds investigated in this review regarding their anti-inflammatory and chondroprotective potential in the context of OA are presented in Scheme 4, while the main effects and research characteristics are summarized in Table 2 Schisandrae Fructus (SF), the dried fruit of Schisandra chinensis (Turcz.) Baill. (Magnoliaceae), is another natural product, traditionally known in the Chinese culture, but also popular in the Russian culture, yet widely used as a folk remedy for the prevention and management of several chronic inflammatory diseases [87]. SF extract in the setting of IL-1β-stimulated SW1353 chondrocytes actively attenuated IL-1β-induced expression of matrix MMP-1, -3, and -13, while the intervention also reduced the elevated levels of COX-2 and iNOS associated with PGE 2 and NO production [88]. In addition, a 2015 study showed that SF markedly suppressed the nuclear translocation of NF-κB by blocking inhibitor κB-alpha degradation and exhibited repressive properties of c-Jun N-terminal kinase and p38 MAPK phosphorylation [88].

Pure Natural Compounds
Over the last decade, numerous compounds isolated from natural products have been investigated in the context of inhibiting inflammation in osteoarthritis. Here, we presented a summary of these findings, mostly based on research conducted in chondrocytes and some OA animal models. Among others, compounds like curcumin, also known as turmeric, with well-documented effects against some conditions, including arthritis [89][90][91]; thymoquinone, a compound isolated from fennel flower (Nigella sativa); representatives of flavonoids (anthocyanins (malvinidin), flavones (chrysin), and flavonols (astragalin and isorhamnetin); geniposide, an iridoid glycoside, with some affiliations against a variety of chronic inflammatory conditions [92,93]; the secoiridoid glycoside oleuropein; the well-known bioactive compound resveratrol, with many biological properties [94] and specific inhibitory properties of NF-kB, as well as COX-2 gene expression and enzyme activity [95], and the equally known rosmarinic acid with also numerous therapeutic assets [96] are included in this review. The chemical structures of all the compounds investigated in this review regarding their anti-inflammatory and chondroprotective potential in the context of OA are presented in Scheme 4, while the main effects and research characteristics are summarized in Table 2.
biological properties [94] and specific inhibitory properties of NF-kB, as well as COX-2 gene expression and enzyme activity [95], and the equally known rosmarinic acid with also numerous therapeutic assets [96] are included in this review. The chemical structures of all the compounds investigated in this review regarding their anti-inflammatory and chondroprotective potential in the context of OA are presented in Scheme 4, while the main effects and research characteristics are summarized in 13. 14.

Curcumin
Curcumin (Scheme 4), also known as turmeric, is a compound with potential protective effects, i.e., against cancer, Alzheimer's disease, heart failure, diabetes, and arthritis [89][90][91]. Focusing on gene expression profiling in human T98G neuroglia cells, a 2018 study showed that supplementation with curcumin and with curcumin-Boswellia serrata combination formula selectively down-regulated opioid-related nociceptin receptor 1 (OPRL1) expression (5.9-fold and 7.2-fold, respectively), which, according to this study, inhibited nociceptin opioid peptide (NOP) production. Further findings of these interventions suggest an essential reduction of neuropathic pain, neuroinflammation, and suppressed a disintegrin and metalloproteinase (ADAM) metallopeptidase gene ADAMTS-5 expression (11.2-fold and 13.5-fold, respectively) [97]. Similar outcomes were observed after supplementations with a ginger/curcumin combination in MIA-induced OA rats. In

Geniposide
Geniposide (Scheme 4), an iridoid glycoside purified from fruits (most well-known Gardenia jasminoides) and herbs, has been commonly used in folk medicine for many chronic inflammatory conditions [92,93]

Oleuropein
Oleuropein (Scheme 4), a secoiridoid glycoside that is the methyl ester of 3,4-dihydro-2H-pyran-5-carboxylic acid, is considered as the most prevalent phenolic component in olive leaves and seeds, pulp and peel of unripe olives with potent anti-inflammatory effects. As reported by an early 2017 study, oleuropein treatment (doses: 10 µM, 50 µM, and 100 µM) on human OA chondrocytes largely inhibited the IL-1β-induced production of NO, PGE 2 , COX-2, iNOS, MMP-1, MMP-13, and ADAMTS-5. Additional findings have introduced the preventative characteristics of this compound against the degradation of aggrecan and collagen-II, as well as inhibitory effects on NF-κB and MAPK activation, suggesting that potential therapeutic effect of oleuropein on OA is due to its effect on those signaling pathways [101].

Flavonoids
Representatives of flavonoids (anthocyanins -malvinidin), flavones (chrysin), and flavonols (astragalin and isorhamnetin) have also been studied in the context of OA. Namely, the main anthocyanins found in three Thai purple rice cultivars (mostly found as 3-glucosides of peonidin and cyanidin) attenuated the inhibition of porcine cartilage degradation in an experimental model, as well as the induction of MMPs caused by IL-1β-stimulated human chondrocytes. Notably, the effects observed to be anthocyanin concentration-dependent, while protocatechuic acid, anthocyanin metabolite, exhibited chondroprotective potential by reducing glycosaminoglycans and collagen (COL) breakdown in IL-1β/ Oncostatin M (OSM)-induced porcine cartilage explants [105]. • Promotes increased production of collagen II • Decreases the expression of proapoptotic molecules-Bax, Cyto-c, and C-caspase 3 • Increases Bcl-2 expression     Malvidin (Scheme 4) (one of the most widespread anthocyanidins) exhibited significant pain-relieving effects in MIA-induced OA Wistar rats and decreased the expression level of apoptotic marker senescence-associated beta-galactosidase (SA-beta-gal) in chondrocytes. It is worth noting that this treatment remarkably reversed the up-regulated expressions of IL-1β, IL-6, TNF-α, and MMPs in cartilage tissues. Furthermore, malvidin suppressed the NF-kB pathway via an NF-kB inhibitor (IκBalpha)-independent manner through decreasing p65 nuclear transportation [106].
Astragalin (Scheme 4), a bioactive compound found in Rosa agrestis, demonstrated anti-inflammatory properties in IL-1β-stimulated human OA chondrocytes. The outcomes of a 2015 study demonstrated that astragalin was able to dose-dependently inhibit IL-1β-induced NO and PGE 2 production, as well as iNOS and COX-2 expression, IL-1β-induced NF-κB and MAPK activation in human OA chondrocyte, by activating the peroxisome proliferator-activated receptor gamma (PPAR-γ) [108]. Similar effects were reported for isorhamnetin (Scheme 4)-a flavonoid mainly derived from the fruit of Hippophae rhamnoides L [109]. Pre-treatment with this compound actively suppressed the expression of stromelysin-1 and collagenase-3, NO, PGE 2 , iNOS, and prostaglandin G/H synthase 2 in chondrocytes. Furthermore, this treatment, as seen in astragalin, also inhibited the expression of NF-κB and transcription factor p65 [109].

Resveratrol
Polyphenols have been extensively investigated concerning their antioxidant, anti-inflammatory, and immunomodulant properties in many inflammatory chronic conditions. Resveratrol (Scheme 4) is a phytoalexin found in particularly high concentrations in grape skin and red wine. Notably, red wine is a widely consumed beverage with many biological properties, including protective effects against oral infections and related bone (osteoarthritis, osteomyelitis, periprosthetic joint infections) and cardiovascular diseases [94].
Resveratrol is, among the bioactive compounds present in wine, the most well studied for its strong and specific inhibitory properties on NF-kB, as well as COX-2 gene expression and enzyme activity [95]. Early 2008-09 studies reported that resveratrol, like N-Ac-Leu-Leu-norleucinal (ALLN), suppressed IL-1β-induced proteasome function and the degradation of IκBα without affecting IκBα kinase activation, IκBα-phosphorylation, or IκBα-ubiquitination. Finally, there is also evidence for resveratrol's suppressing ability on IL-1β-induced apoptosis, caspase-3 activation, and PARP cleavage in human articular chondrocytes [110][111][112].
A 2017 study aimed to evaluate the biological effects of resveratrol implicated in human chondrocytes stimulated with IL-1β involving both dependent and independent toll-like receptor-4/myeloid differentiation primary response 88 (TLR4/MyD88) signaling pathways. Co-treatment with resveratrol was able to reduce the cell viability of IL-1β-stimulated chondrocytes. Besides, while IL-1β stimulation increased the upregulation of TLR4 and downstream targets in both dependent and independent TLR4/MyD88 signaling pathways, co-treatment with resveratrol suppressed both catabolic and inflammatory responses in a dose-dependent manner. Resveratrol reduced the expression levels of MMP-13, IL-6, TNF-α, phospho-interleukin-1 receptor-associated kinase 4 (p-IRAK4), and TLR4-tumor necrosis factor receptor-associated factor 6 (TRAF6) mediators of the TLR4/MyD88 signaling pathways [113]. Similar results were observed in obesity-related OA in an animal model. The overall outcomes of this 2017 study indicate that high-fat diet-induced obesity could trigger the onset of OA, and resveratrol might alleviate OA pathology by decreasing systematic inflammation and/or inhibiting the TLR4 signaling pathway in cartilage, posing as a potential therapeutic approach for obesity-related OA [114]. Limagne E. et al. investigated the pro-inflammatory paracrine interactions between human primary chondrocytes and macrophages following IL-1β treatment. Resveratrol showed a strong inhibitory effect on the pro-inflammatory marker secretion, which was dependent on NFκB inhibition in the chondrocytes [115].
The accumulation of advanced glycation end products (AGEs) in joints contributes to the pathogenesis of cartilage damage in OA. In the setting of AGEs-stimulated porcine chondrocytes and cartilage explants, a 2010 study showed that AGEs-induced expression of iNOS and COX-2 and production of NO and PGE 2 were suppressed by resveratrol. This study suggests that the effects of this treatment were likely mediated through inhibiting IKK-IκBα-NF-κB and c-Jun N-terminal kinase/Extracellular signal-regulated kinases-Activated protein-1 (JNK/ERK-AP-1) signaling pathways. By targeting these critical signaling pathways, resveratrol decreased AGEs-stimulated expression and activity of MMP-13 and prevented AGEs-mediated destruction of collagen II. Histochemistry analysis further confirmed that resveratrol could prevent AGEs-induced degradation of proteoglycan and aggrecan in cartilage explants, providing additional evidence to the potential therapeutic benefit of resveratrol in the treatment of OA [116].

Rosmarinic Acid
Rosmarinic acid (Scheme 4), most well known for being the active ingredient in Rosemary, presents a number of interesting biological activities, e.g., antiviral, antibacterial, anti-inflammatory, and antioxidant [96]. Reports from a 2017 study suggest that rosmarinic acid increased type II collagen, sulfated-proteoglycan, COX-2, and PGE 2 production in a dose-and time-dependent manner in rabbit articular chondrocytes while suppressing the expression of MMP-13. The treatment also activated extracellular signal-regulated kinase (ERK)-1/2 and p38 kinase signaling pathways [117]. Similar results were observed in rat IL-1β-stimulated chondrocytes, where IL-6 production was inhibited, as well as the gene and protein expression of ADAMTS-4, ADAMTS-5, aggrecan (ACAN), and type II collagen, overall suggesting, as previously observed, that rosmarinic acid could inhibit extracellular matrix (ECM) degradation in OA [118].

Other Phenolics
Schisantherin A (SchA) (Scheme 4) is a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera. In the setting of IL-1β-induced OA chondrocytes, treatment with this compound significantly inhibited NO, PGE 2 , and TNF-α production in a dose-dependent manner. Moreover, IL-1β-induced MMP-1, -3, and -13 expression and NF-κB and MAPKs activation were essentially suppressed [119]. Similar results were observed in the case of diosgenin (Scheme 4), which is a steroidal saponin found in several plants, including Solanum and Dioscorea species. Diosgenin was found able to additionally inhibit the expression of COX-2 in human OA chondrocytes and suppress the degradation of IκB-α [120]. Additionally, MMP-3 and MMP-13 expression, phosphorylation of p-38, extracellular regulated kinase (ERK), c-Jun-N-terminal kinase (JNK), and IκB-α degradation induced by IL-1beta in chondrocytes were significantly curbed by Matrine, an alkaloid found in plants from the genus Sophora. This compound, which also acts as a κ-opioid and µ-opioid receptor agonist, significantly inhibited the IL-1β-induced apoptosis in chondrocytes, while it increased the production of TIMP-1 [121].

Acacia catechu and Mori folium Standardized Blend (UB1306)
Acacia catechu (Mimosa family) extracts and Mori folium, the leaves of Morus alba L., have been traditionally used as a dietary supplement or folk medicine due to the documented anti-inflammatory activity, as well as protection of the liver and hypertension, respectively [122]. The aqueous extract of Acacia catechu heartwood is a good source of catechin and epicatechin, with smaller quantities of flavonoids, which have well-documented health benefits [123], also in the context of OA as it has been observed in this review. In a randomized, double-blinded, placebo-controlled, parallel design, 135 subjects received UP1306 (a standardized blend of Acacia catechu and Mori folium), glucosamine chondroitin, or placebo for 12 weeks in an effort to determine the effects of UP1306 on discomfort and function in adults with OA of the knee. The outcomes displayed an improvement in discomfort, stiffness, and daily activity (WOMAC questionnaire and Visual Analog Scale (VAS) score) within all groups. Namely, the Western Ontario McMaster universities osteoarthritis index (WOMAC)-pain sub-score was decreased by 51% for UP1306, by 45% for glucosamine chondroitin, and by 46% for placebo. Although there were no changes in TNF-α levels, a notable difference in urinary C-telopeptides of type II collagen (CTX-II), a marker of cartilage degradation, was observed after 12 weeks (p = 0.029). Notably, serious adverse events (AEs) were not observed in this study. In a sub-group of 30 of the 133 subjects in the safety population, 43 clinically non-significant adverse events were observed (15 in the UP1306 group, 10 in the glucosamine and chondroitin group, and 18 in the placebo group), while only 14 events were considered to be related to the study product [124].

Coriander, Litsea Japonica, and Guilu Erxian Jiao
Coriander (Coriandrum sativum L.), a member of the Apiaceae family, is among the most widely used medicinal plants, possessing nutritional and medicinal properties [125]. Treatment with coriander (C. sativum L.) leaf powder (5 g/day for 60 days) on OA patients suppressed LOX and catalase activity (CAT) in erythrocytes as well as alkaline phosphatase activity and erythrocyte sedimentation rate (ESR) while improving serum β-carotene, vitamin C, and calcium levels. In addition, increased activities of glutathione-S-transferase (GST) and decreased glutathione (GSH) content were also reported in the treated OA patients [126].

Guilu Erxian Jiao
The initial focus in osteoarthritis is the management of the painful symptoms aside from biochemical markers assessment, and, to that end, natural products, such as guilu erxian jiao, have also been evaluated. Elderly men were included in a 2014 clinical trial in an effort to evaluate the effects of guilu erxian jiao in the context of knee osteoarthritis (KOA). This 12-week study demonstrated overall significant increases in muscle strength and knee flexibility, along with limited pain (p < 0.01) in the intervention group (n = 21) [45].

Litsea Japonica
Litsea is a genus of the Laurel family, Lauraceae, including numerous accepted species found in tropical and subtropical areas. Regarding the efficacy context of this plant (extract) (using low-dose group; dose: 100 mg/d and high-dose group; dose: 200 mg/d), the record showed that WOMAC scores on the pain (p = 0.0293), stiffness (p = 0.0002), and function (p = 0.0152) subscales significantly improved during a 12-weeks randomized, double-blind, placebo-controlled study, involving 87 OA knee patients, underlining dose-dependency of the outcomes [58].

Maslinic Acid
Maslinic acid (MA) (Scheme 4) is a pentacyclic triterpene with a range of biological activities, namely, antitumor, antidiabetic, antioxidant, cardioprotective, neuroprotective, antiparasitic, and growth-stimulating [127]. In a recent 2018 study, Yoon et al. investigated the possible synergetic effects of this compound co-administrated with whole-body vibration training (WBVT), in the context of the knee and muscle function improvement, in elderly women with knee OA. In this double-blinded, placebo-controlled, randomized intervention study, the selected participants (26 females aged 65-85 years with knee OA) had WBVT and were allocated to receive either 16.7 mg of MA or a placebo daily for a period of 20 weeks. The outcomes of whole-body vibration training were compared with the respective placebo (WBVT/P) and MA (WBVT/MA) groups. Based on the results of this analysis on muscle function measurements, positive outcomes were reported in all groups, underlining the significance of a non-invasive (chemical or natural treatment) approach, while there was significant interaction (time × group) (p = 0.03) in the "isokinetic extension peak torque" domain for severe OA (Kellgren and Lawrence (K-L) grade ≥ 3) [128]. Moreover, in the setting of an open-label clinical trial, daily consumption of a MA-containing product (30 mg MA) for a period of 16 weeks improved the physical quality of life, level of bodily pain, and physical component, but not mental quality of life in a total of 29 elderly (mean age: 70.7 ± 10.1 years) participants [129].

Pomegranate
Pomegranate extracts have been found to have strong anti-inflammatory, antioxidant, and even antitumor properties in vivo and in vitro, while there is also some evidence supporting this natural product in a clinical setting. Namely, data from a placebo-controlled trial showed that the intervention (500 mg of pomegranate peel, hydro-alcoholic extract) increased Knee injury and Osteoarthritis Outcome Score (KOOS) mean from 46.15 ± 16.82 to 57.57 ± 15.61 after 12 weeks (p < 0.001) as compared to the placebo group (baseline: 50.83 ± 18.83, after 12 weeks: 56.10 ± 18.07) (p < 0.001), while the VAS score remarkably declined in both arms compared with the respective baselines (p < 0.005) [130]. Similar results were observed in a smaller scale study involving 38 patients with knee OA, who were allocated to receive pomegranate juice and placebo for 6 weeks. This 2016 study showed that the WOMAC index total score (p = 0.01), stiffness score (p = 0.00), and physical function score (p = 0.01) were scientifically decreased in the intervention group, as well as the means MMP-13 levels (p = 0.02), while glutathione peroxidase was increased (p = 0.02) [131].

Spearmint (Mentha spicata)
Mints (Mentha sp.) have been among the most widely used aromatic plants for food flavoring, tea preparation with anti-inflammatory, anti-carcinogenic, antioxidant, and anti-peroxiding properties [132]. The potential of a high-rosmarinic acid (rosA) spearmint tea was studied in the setting of a randomized, double-blind study on KOA patients. Data from 46 participants (mean age = 60.7; BMI = 32.9 kg/m 2 ) showed that pain score considerably decreased from week 0 to 16 for the high-rosA group instead of the control group, as well as scores for physical disability and stiffness for both groups. Additionally, increased quality of life (QoL) score on the bodily pain index in the SF-36 was observed at week 16 within the high-rosA group only, as well as a non-significant improvement in the six-minute walking test (6MWT) [133].

Turmeric (Curcuma domestica) (Curcuma longa)
Turmeric (curcumin) is generally considered the most biochemically effective compound derived from the rhizomes of Curcuma spices [134]. A 2014 study, involving 367 primary KOA patients randomly assigned to an active comparator or C. domestica extracts for 4 weeks, showed overall improvement in WOMAC scores of the treatment group versus the baseline, while events of abdominal pain/discomfort were more often in the ibuprofen (positive control) group (p = 0.046), and most of the participants declared improvement of their overall status [135]. In a recent study, KOA participants (n = 40) were divided to receive encapsulated curcuminoids (1500 mg/day*3; n = 19) and placebo capsules (n = 21) [136]. This 6-week intervention with curcuminoids showed an increase in glutathione levels (p = 0.064) and SOD activity (p < 0.001) in serum [136]. A summary of the overall clinical findings of this review is presented in Table 3. Table 3. Clinical trials investigating the effects of natural products and compounds in OA (Summary).  -WOMAC -pain decreased from baseline in the treatment group (p = 0.002) -WOMAC -stiffness decreased from baseline in the treatment group (p = 0.004) -WOMAC -physical disability decreased from baseline in the treatment group (p = 0.02) -WOMAC scores on all scales were not significantly different between groups -SF-36 QoL score (bodily pain) increased from 46.6 ± 7.6 (baseline) to 58.1 ± 22.1 (week 16) in the treatment group (p < 0.05) -Six-minute walk test change from baseline was +22.3 m for the treatment group and +0.1 m for the control group with no significant differences within or between groups -Overall, no serious adverse events reported -AEs in treatment group: constipation (n = 3), headache (n = 2), loose bowel movements (n = 1) -AEs in control group: staining of dentures (n = 1), dry mouth (n = 1), itchy skin (n = 1) [133]  -Muscle function: isokinetic extension peak torquetime * group interaction (p = 0.03), effect sizes were higher in the treatment group for all domains of muscle function -Knee function: time was a significant factor in the domain of "pain on ascending or descending stairs" (p < 0.01) Kellgren and Lawrence (K-L) grade had a main effect in "pain on walking" (p = 0.04) and "range of motion" (p < 0.01) -Performance of WBVT program: Participants in the treatment group attended 422 of 440 training hours Participants in the control group attended 581 of 600 training hours

Discussion
In this study, we evaluated the literature over the last decade regarding the potential anti-inflammatory role of natural products against osteoarthritis. We evaluated all the references regarding natural products and pure natural compounds (using in vitro, in vivo, ex vivo data, and animal models) and clinical trials on humans.
This review overall presented the findings of almost 90 published papers, most of which documented the anti-inflammatory properties of natural products and natural compounds in vitro. A total of 17 natural products and 14 isolated compounds are found to have reported anti-inflammatory and/or chondroprotective activity, along with properties of pain reduction and physical function improvement.
More specifically, in 59 studies, 12 natural products and 13 pure natural compounds were evaluated in vitro, mostly by employing assays on RAW 264.7 or chondrocytes, while, in three of them, the pure compounds were studied via animal models. One study presented ex vivo results.
At the molecular level, the inhibition of several inflammatory mediators (MMPs, PGE 2 , IL-6, NO, iNOS, COX-1-2, LOX, and TNF-α, to name a few) and NF-κB and MAPKs pathway activation are commonly found among the results of in vivo findings; however, others, such as NOP, SOD, MDA or TIMP-1, COMP, MPO, OPRL1, and ADAMTS-4-5, are not frequently assessed. This might be a key indicator as to why much promising natural products or compounds based on in vitro and in vivo findings tend to fail in clinical trials. On that note, curcumin, resveratrol, maslinic acid, and some anthocyanins are bright examples of the opposite, with occasionally limited yet crucial clinical evidence of their effects against osteoarthritis.
An interesting remark regarding the action of all these different compounds, at a molecular level, is the observation of a not so diverse impact on such a vast variety of molecules. On that note, C-terminal telopeptide of collagen type II has been one of the most frequently assessed biomarker of collagen metabolism, and cartilage oligomeric matrix proteins (COMP and its deamidated form D-COMP) and matrix metalloproteinases (MMP-1, MMP-3, MMP-9, MMP-13, and TIMPs) have been the most well-known biomarkers related to other non-collagenous proteins and regarding biomarkers related to other processes; the inflammatory biomarkers IL-1β, IL-6, and COX-2 have been mostly evaluated. However, also significant biomarkers in OA, such as type II collagen pro-peptides (PIINP, PIIANP, PIIBNP, PIICP, CPII), pyridinoline, Glc-Gal-PYD, collagen type II-specific neoepitope (C2M), N-terminal telopeptide of collagen type I (NTX-I), core protein fragments (aggrecan neoepitopes, ARGS(amino acids alanine (Ala; A), arginine (Arg; R), glycine (Gly; G) and serine (Ser; S); N-terminal sequence created by aggrecanase cleavage), and FFGV fragments), fibulin (peptides of fibulin 3, Fib3-1, Fib3-2), follistatin-like protein 1 (FSTL-1), soluble receptor for advanced glycation end-products (sRAGE), adipokines (adiponectin, leptin, visfatin), soluble receptor for leptin (sOB-Rb), cellular interactions in bone (periostin), and Wnt inhibitors (DKKs and SOST) are rarely evaluated. Additionally, as previously reported, only the NF-kappa B, the Phosphatidylinositol 3-kinase/ Protein kinase B (PI3K/Akt), and the MAPK signaling pathways have mostly been considered for analysis as the most well-known pathways in the development or progression of OA. However, research has shown that there might be a lot more to explore than these, namely, the renin secretion, apoptosis, the TNF signaling pathway, calcium reabsorption, the cGMP-Protein kinase G (PKG) signaling pathway, the adipocytokine signaling pathway, the estrogen signaling pathway, glycerophospholipid metabolism, the thyroid hormone signaling pathway, and the cAMP signaling pathway. The understanding of this elaborate network of pathways and implicated biomarkers in the progression of osteoarthritis can unravel the targets of the different natural products or compounds with a hope to highlight their true therapeutic potential.
In a total of 12 clinical trials, three natural compounds and eight natural products were evaluated, mostly against placebo and, in some cases, against active comparators (i.e., ibuprofen) for intervention periods ranging from 4 to 20 weeks. It is remarkable that in all cases, there was the oral treatment of either the natural products or the pure natural compounds. Natural occurring products present significant advantages in oral treatment in terms of safety and bioavailability, which has to be further investigated for their potential use in prevention and treatment against osteoarthritis.
Considering that inflammation and pain are the major problems for OA patients, particularly for those with knee osteoarthritis, which can dramatically affect the quality of life, several investigations are focusing on this area, hoping to provide solutions. The utilization of complementary and alternative medicine in the treatment of a variety of medical conditions is an increasingly observed phenomenon. The clinical use of nutritional modulators as a treatment of pain has already been widely studied in cases of myalgias, rheumatoid arthritis, menstrual pain, and osteoarthritis. Although some nutritional modulators are endorsed via scientific research for their ability to contribute or treat in a variety of pain and inflammation states, others (including turmeric, devil's claw, methylsulfonylmethane (MSM), Boswellia, white willow bark, and green tea) have contradictory or minimal evidence to support their use for inflammation relief. Despite the medical evidence or lack thereof, passionate consumers continue to utilize these modulators as supplements or alternatives to conventional pharmacotherapy [139].
It is interesting to be mentioned that most of the natural products, as well as the pure natural compounds, have already been further evaluated for other biological activity, providing a multi-target profile, which has to be considered for further utilization of natural products.

Conclusions
Our work has highlighted the need for consistency in the findings, which can only be achieved through a deeper understanding of the mechanisms involved in the development of OA and those that nutritional mediators can affect, by also considering dose and time factors. Given the significant content of dietary polyphenols and other natural products in the typical human diet and the potential of dietary supplements, more well-designed human clinical trials are needed to evaluate the effects of natural products and compounds thereof on OA in terms of functional, structural, and biochemical outcomes.