Unravelling the Approaches to Treat Osteoarthritis: A Focus on the Potential of Medicinal Plants

Background: Osteoarthritis (OA) is the most prevalent chronic rheumatic disorder, affecting more women than men. The prevalence and course of OA are increased by ageing and obesity. Numerous other risk factors for OA progression include oxidative stress, injury, mechanical stress


INTRODUCTION
Arthritis is the major cause of disability and joint pain in the elderly, and it is the most prevalent health condition in the world.The most prevalent sites of inflammation are the knees, feet, hands, hips, and lower back.Rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most frequent forms of arthritis, although there are many more OA.Both deteriorate joint structures and produce excruciating pain, but their signs, causes, and treatments are very different.When the immune system assaults and inflames the joints, it is known as RA.When it comes to osteoarthritis, however, it's all about the deterioration of the articular cartilage as well as changes in the structure of the articular system. [1] is the most prevalent chronic rheumatic disorder and affects women more than men.Ageing and obesity, and many more factors like oxidative stress, injury, mechanical stress, and metabolic disorders increase the prevalence, and progression of OA.Influence OA progression.It is characterised by cartilage degeneration and synovitis changes (Figure 1).OA affects mainly the knee joints, and it is estimated that around 12% of patients are concerned with knee OA, 6.8% affects with OA of the hands, and about 9.2% are affected by OA of the hip joint. [2]OA influences the quality of a patient's life by the loss of physical structure and the failure of all joint functions.In OA, the most prominent is loss of articular cartilage, but a synovial membrane, subchondral bone, and ligaments are also affected.On the cellular level, catabolic functions of chondrocytes overcome the anabolic processes of chondrocytes which pro-inflammatory mediators stimulate.These mediators are localised in synovial fluid and stimulate the production of enzymes like collagenase and aggrecanases, which degrade collagen, and proteoglycans.There are several mediators, such as IL-1, NO, TNF-, PGE2, NF-B, and mitogen-activated protein kinase signalling pathways, that play an important part in the pathophysiology of OA.Pain, soreness, and stiffness are all indications of OA, which progresses slowly. [3,4]teoarthritis is a debilitating disease that has few effective therapeutic options.Osteoarthritis is now treated with NSAIDs, an opioid analgesic, a topical analgesic, and intra-articular steroids to reduce pain, and symptoms.There are several side effects associated with all these treatments, including gastrointestinal, cardiovascular, and nephrotoxicity, tramadol, indomethacin, and NSAIDs, which all limit their use in OA. [5,6] As a result, patients began to express an interest in herbal plants due to concerns regarding safety, and effectiveness.Aside from that, people have relied on plant-based medications for centuries because of the lower risk of adverse effects.For this reason, a variety of herbal medicines were used.Even so, they don't completely treat OA, but they may be quite successful if the proper diet, and therapy are used.The pain and inflammation associated with OA may also be reduced by using some medicinal herbs. [7,8]Herbal plants as a treatment option for OA are the focus of this review, which intends to offer current research, and demonstrate the potential of medicinal plants to alleviate OA symptoms.

Pathophysiology
OA is the most common type of joint disorder.It is a worn and tears disease.The excessive reaction of chondrocytes and inflammatory mediators is responsible for the breakdown of articular cartilage in OA pathogenesis.In addition to cartilage and the synovial membrane, OA affects bones, and the subchondral bone. [9]eps involved in the degradation of articular cartilage: stage 1 involves the breakdown and conversion of cartilage proteins into amino acids and polypeptides takes place.Fibrillation or erosion occurs as a result of protein fragments leaking into the synovial fluid in stage 2. Articular cartilage is further degraded by the first two stages of inflammation.
Articular cartilage, also known as hyaline cartilage, is located at the ends of bones, and is affected by OA.In cartilage, collagen, and glycosylated proteins are the primary building blocks that hold the tissue together.The cartilage also contains chondrocytes. [10]When there is an inflammatory reaction, interleukin-1 is released, which damages cartilage.IL-1 is linked to the release of protease enzymes that further breakdown cartilage.TNF-alpha-like cytokines cause joint injury by activating the enzyme matrix metalloproteinases (MMPs).Colloidal collagenase is another enzyme that degrades articular cartilage (Figure 2). [11]e synovial membrane has an effect on the synovial fluid since it is a connective tissue.Inflammation of the membrane occurs as a result of cartilage injury.The articular cartilage is further damaged by synovial macrophages, which cause inflammation. [12]

MATERIALS AND METHODS
Google Scholar, PubMed, and Scopus were used as academic search engines in the literature search.Essential oils, arthritis, antiarthritic, anti-rheumatoid arthritic activity, herbal plants, and chondroprotective agents were searched for in the databases.Studies on the antiarthritic properties of herbal plants, whether as whole plants, or as isolated active ingredients, are included in this review study.

Potential medicinal plants for osteoarthritis treatment
Plants have long been used to treat a variety of illnesses, and a number of different plants have showed promise as OA-treating options.Plants may contain a bioactive component that reduces OA discomfort and development, according to several research.To treat various forms of arthritis, several species of plants have bioactive chemicals that may be extracted using alternative solvents (Table 1).
There are a number of plants that have the potential to cure OA, including Boswellia serrata, a member of the Burseraceae family, commonly known as salai.Different phytochemicals including monoterpenes (-thujene, -pinene, cis-verbena, transpinocarveol), diterpenes (Incensole and iso-inconsole oxide), triterpenes (-amyrins), Boswellia acids, and tetracyclic triterpenic acids are found in the plant [13] Research demonstrates that Boswellia serrata extract includes boswellic acid, a molecule that has been shown in trials to have OA-fighting properties.[16] Boswellic acid was advised by the Arthritis Foundation to be taken in doses of 300-400 mg per day of Boswellia.OA may benefit from a combination of boswellic acid and curcumin, according to some research. [17]0] Known as Du Zhong, Eucommia ulmoides is a tough rubber tree from the Eucomiaceae family.Lignans, iridoid glycoside, phenolic compounds, -sitosterol and daucosterol, ulmoprenol and betalin, betulic acid, and ursolic acid are among the active phytochemicals found in the plant. [21]E. ulmoides' leaves and bark have been shown to have anti-OA properties.The phosphoinositol 3-kinase pathway prevents cartilage deterioration and reduces the production of inflammatory cytokines in E. ulmoides extract, however its effectiveness for OA is limited.4] Cat's claw, or Uncaria tomentosa, is a pharmacologically active plant of the Rubiaceae family.Fever, UTI, viral infections, and wounds have all been traditionally treated with this herb, which contains anti-inflammatory alkaloids, flavonoids, sterols, and glycosides. [25,26]The cat's claw may also help alleviate osteoarthritis.Rhynchophylline (Figure 3b) is an indole alkaloid found in U. tomentosa extract that has been shown in studies to have substantial antioxidant and anti-inflammatory effects. [2,27,28]hwagandha, a member of the Solanaceae family, is a popular name for Withania somnifera.Among the active phytochemicals in Ashwagandha include withanolide A, withanone, withanolide D, as well as alkaloids, flavonoids, steroids, and zingerone. [29]For OA and RA, W. somnifera has been utilised since ancient times.Due to withanolide, aqueous W. somnifera roots extract exerts a protective effect (Figure 3c). [30]Withanolide, a compound derived from W. somnifera, is often used in ayurvedic medicine to treat OA, and RA.3] The Chinese herb Angelica sinensis, sometimes known as female ginseng, is a member of the Apiaceae family.A. sinensis root extract contains the secondary metabolite ligustillide (Figure 3d) that is responsible for the plant's anti-arthritic activity. [34,35]igustillide reduced the levels of p65, IKK/, and IKK/, and decreased the expression of MMP-3, ADAMTS-5, iNOS, and COX-2, according to the results of a series of studies.Also, it suppresses the IL-1β induced degradation of collagen and aggrecan. [36,37]ycyrrhiza glabra, sometimes known as licorice, or mulaithi, is a legume in the family Leguminosae.There are several traditional uses for G. glabra, including treating coughs, colds, and swelling, as well as acting as a diuretic, and pesticide. [38]G. glabra contains active secondary metabolites like glycyrrhizin, flavonoids, saponoids, sterols, starches, amino acids, gums, Liquiritin, glabridin, glabrene, liquiritigenin, glabrolide, isoglabrolide, liquiritic acid, glypallidifloric acid, glycyrretol (glycyrrhetol), liquiridiolic acid. [39,40]Glycyrrhizin, a chemical extracted from the root of the plant, has also been linked to OA.There are anti-inflammatory and anti-collagen degradation effects of glycyrrhizin (Figure 3e).In addition, studies show that glycyrrhizin protects the chondrocytes in OA. [41][42][43][44] Saposhnikovia divaricate is a perennial plant from the Umbelliferae family that may be found throughout North Asia.Various active phytochemicals in the dried root of this plant have been used to treat nervous system, immune system, and respiratory diseases.Examples include: isobergapten, imperatorin, pentacosane acid, anomalin, decision, 5methoxy-7-(3,3-dimethylallyl-oxy) coumarin, decursinol angelate, xanthotoxin, bergapten, tectochrysin, scopoletin, hamaudol, ledebouriellol, cimifugin, sec-O-glucosylhamaudol, 4'-O-beta-D-glucosyl-5-O-methylvisamminol, and prim-O-glucosylcimifugin. [45,46]For OA, S. divaricate is mainly used for inflammation by inhibiting the production of cytokines and also protecting cartilage. [44,45]mellia sinensis is, commonly known as green tea, belongs to the family Theaceae.Bioactive chemicals found in tea plants have a significant impact on the cosmetics sector.Bioactive substance Epigallocatechin-3-gallate (Figure 3f) has a potential for the treatment of osteoarthritis (OA). [47]Research shows that it inhibits chondrocytes' release of lactate dehydrogenase.0][51] Ribes nigrum, more often known as blackberries, provide a wide range of beneficial compounds for human health.There are many flavonoids in black barriers that are beneficial to health, including rutinosides, pelargonidin, cyanidin, peonidin, delphinidin, prodelphinidins, petunidin, and malvidin, cyanidin 3-O-arabinoside, delphinidin, anthocyanins, myricetin-3-O-glucoside, flavan-3-ols, hydroxycinnamic acids, myricetin aglycone, gallocatechin, epigallocatechin. [52]In addition, the leaves extract of R. nigrum contains the compound prodelphinidins (Figure 3g), having significant potential.Some trials show that prodelphinidins have an inhibition potential on cyclooxygenase in-vitro. [52,53]ppan wood is the common name for a species of Caesalpinia sappan, a member of the Leguminosae family.To treat bloodrelated diseases including dysmenorrhea, amenorrhea, and pain from external injuries, C. sappan is often used in TCM (Traditional Chinese Medicine).Glycosides, ß-amyrin, glucose, brazilin, caesalpin J and P and protosappanin A, and B, homoisoflavonoids ß-sitosterol, sappanol, episappanol, quercetin, rhamnetic and brazilein, and brazilin are some of the phytochemicals found in C. sappan. [54]6] Pinus pinaster contains pycnogenol, a US-registered name for a product having anti-inflammatory, and chondroprotective supplements.Pycnogenol is extracted from the Pinus plant that belongs to the family Pinaceae.Commonly known as maritime pine and contain various bioactive chemicals like Glycoside, ß-amyrin, glucose, brazilin, caesalpin J, caesalpin P, protosappanin A, protosappanin B, homoisoflavonoids ß-sitosterol, sappanol, episappanol, quercetin, rhamnetic, brazilein, brazilin. [57,58]However, pycnogenol, which is extracted from plants, has been shown to have chondroprotective effects in cartilage, and to help avoid the pain associated with OA. [59][60][61] Betula platyphylla, a member of the Betulaceae family, has been linked to osteoarthritis.Subarctic and temperate Asia, including Japan, Russia, Korea, and China are home to this species.Proteoglycan breakdown is prevented by inhibiting the expression of MMP-3 and MMP-13. [62]Triterpenoids, diarylheptanoids, phenylbutanoids, flavonoids, catechins, and steroids are only a few of the plant's other active phytochemicals. [63,64]ngamia pinnata is a monotypic species belonging to the family Papilionaceae.It is widely distributed and has potential for different diseases, also showing potential for OA.P. pinnata contain very effective phytochemicals like Sterols, beta-sitosteryl acetate, galactoside, stigma sterol, galactoside, stearic acid, palmitic acid, Karangin, pongamol, pongagalabrone, pongapin, pinnatin, kanjone, pongol, Glabrachalcone, isopongachromene, Galbone, Pongalabol, pongagallone A. [65] According to research, hydroxyproline in the urine and other mediators of collagen, and cartilage breakdown are reduced, as are the lysosomal enzymes responsible for cartilage destruction.7] Commiphora mukul is commonly known as guggul belonging to the family Burseraceae.It's found in dry regions of India, and gum resin has the potential to treat OA.Guggul contains bioactive compounds like guggulsterol, guggulsterone, flavonoids, and coumaric acids.In OA, guggul prevents the chondrocytes breakdown. [33,68,69]yllanthus amarus Schum, commonly known as Bhumi amla, is a small herb having potent medicinal values, and is used worldwide.In the Indian ayurvedic system, P. amarus is reported crucial medicinal plant to treat various diseases associated with the stomach, kidney, liver, spleen, and genitourinary system.The whole plant has a therapeutic value and contains alkaloids (Securinine, nor-securinine, epibubbialine, isobubbialine, dihydrosecurinine), flavonoids, tannins, lignanins, and sterols. [70]In addition, it exhibits antiarthritic activity, and is beneficial in OA.Furthermore, some major compounds like phyllanthin, and hypophyllanthin (Figure 3i) show the chondroprotective potential for OA. [71,72]oe barbadensis miller, common name aloe vera belonging to the family Asphodelaceae.Because of its many health benefits, Aloe vera has been utilised since antiquity for everything from skin care to wound healing to sunburn relief.Aloe barbadensis miller contains secondary metabolites like anthraquinones (aloe-emodin, aloetic-acid, anthranol, barbaloin, isobarbaloin, emodin, ester of cinnamic acid), carbohydrates (acetylated glucomannan, glucogalactomannan, galactan, galactogalacturan, arabinogalactan, galactoglucoarabinomannan, pectic substance, xylan, cellulose), C-glucosyl chromone, and inorganic compounds having potential for different pharmacological activity, [73,74] and widely used in the cosmetic industry but it also shows potential for arthritis.C-glucosyl chromone (Figure 3j) is the main component from aloe vera extract showing anti-inflammatory activity and helping in reducing inflammation due to arthritis. [75,76]psaicin (Figure 3k) is extracted from plant Capsicum annuum used topically for OA pain.It is a marketed formulation that directly applies to the skin (topical analgesic).Capsaicin reduces joint pain when rubbed over affected joints. [25,77]e chamomile plant, Matricaria chamomilla, is a member of the Asteraceae family.Traditionally, chamomile has been utilised for its therapeutic benefits for thousands of years.Chamomile has the potential for fever, cough, wound healing, and GIT disease. [78]Apigenin, luteolin, quercetin, Isobutyl angelate, 2methybutyl angelate, farnesene, beta-farnesene, farnesenesol, bisabolol, bisabolol oxide A and B, matricin, Chamazulene, Guaiazulene, and Chamazulene are the primary active components in chamomilla.OA sufferers may benefit from the   Arnica montana (Asteraceae)

Common name
Leopard's bane -Reduces pain Flowers Hydro-alcohol [111][112]  usage of chamomile in their treatment regimens as well.The use of analgesics by individuals with osteoarthritis of the knee has been shown to be reduced when chamomile oil was administered.Chamomile's apigenin (Figure 3l) has also been shown to have anti-OA properties.Cytokine production and MMP-3 expression are reduced by Apigenin. [79,80]coction of the roots of Paeonia lactiflora, which are members of the family Paeoniaceae, and are used to treat inflammatory illness.Peony, chandayra, and Chandra are all frequent names for this flower.Water and ethanolic extract of these plants contain the active compound, i.e., Paeoniflorin (Figure 3m), showing activity for OA.Paeoniflorin in preclinical studies showed activity like alleviating pain, bone erosion, joint swelling, and cartilage degradation in experimental animals.3] Zingiber officinale belonging to the family Zingiberaceae, is commonly known as ginger, and ginger extract has potential for RA.Moreover, its extract has a moderate effect on OA patients by reducing the pain symptoms of OA. [84,85] Mainly in OA, it inhibits the inflammatory mediators, which shows a decrease in pain, and inflammation in OA patients. [86,87]Even, Curcuma longa belonging to the same family Zingiberaceae, commonly known as turmeric, or haldi, has many pharmacological activities.
It is used for a variety of ailments like cancer, neuroprotective, anti-inflammatory, anti-apoptotic, and also used as anti-bacterial due to active phytochemicals like curcumin, demethoxycurcumin, bisdemethoxycurcumin, turmerone, santalene, santalenone, β-sesquiphellandrene terpinolene, curcumenol, curdione, curcumol. [88]Turmeric's curcumin (Figure 3n) has been shown in tests to be useful in treating OA. [89] Curcumin inhibits the inflammatory process by reducing the cyclooxygenase enzyme activity and reducing interleukins.2][93] Justicia gendarussa is a quick growing and evergreen plant belonging to the family Acanthaceae.It is primarily grown in the moist area and widely cultivated in India and Malaysia.It contains an alkaloid, steroid, flavonoid, phenol, carbohydrate, saponin, and quinone stigmasterol, lupeol, ß-sito-sterol, and J. gendarussa used in many diseases from ancient times like used to treat respiratory illness, fever, arthritis, and also used in muscle pain. [94]The plant's ethanolic extract has been shown in recent research to have the ability to cure OA.The MMP-9 and iNOS enzymes are both inhibited by the J. gendarussa extract, which reduces inflammation.In order to manage OA pain, it is most often utilised. [95,96]g rose, also known as Rosa canina, is a traditional remedy for a variety of ailments. [97]Flavonoids (anthocyanins, flavones, flavanols, isoflavones, flavanols, flavanones), carotenoids (lutein, zeaxanthin, and cryptoxanthin, alpha-carotene, beta-carotene, and lycopene), fatty acids (-linolenic acids), vitamins, and triterpenes have all been extracted from the plant.By suppressing the inflammatory mediators and COX enzyme, the R. canina is utilised to treat osteoarthritis.It is mainly used for the pain associated with osteoarthritis pain. [98]perine (Figure 3p) isolated from Piper longum Linn., family Piperaceae is a phenolic compound having the potential for OA.Piperine inhibits the MMP-13 and prostaglandin production in chondrocytes.In rat models, piperine reduces arthritis symptoms, and pain sensation due to OA. [99][100][101] Saussurea lappa clarke, commonly known as kushta has many therapeutic applications.It contains many active compounds like sesquiterpenes, sulfocostunolide A, sulfocostunolide B, saussureamine B, saussureamine C, arbusculin A, β-costic acid, santamarin, reynosin, α-amyrin, α-amyrin stearate, pregnenolone, and lappasterol. [46,102]Preclinical studies showed that Saussurea lappa has anti-osteoarthritic activity by inhibiting the MMP expression and NF-κB signalling pathway in the mice model. [103,104]lix daphnoides known as willow bark is traditionally used for articular pain.Willow bark aqueous and hydroalcoholic extract contain active phytochemical salicin (Figure 3o).Salicin inhibits the cyclooxygenase enzyme and reduces osteoarthritis pain. [93,105]dicated sesame Sesamum indicum commonly known as tila, a member of the Pedaliaceae family, yields sesame oil.Sesame oil is a traditional medicine used as an antioxidant, anti-inflammatory, anti-bacterial, and it contains phytochemicals like unsaturated fatty acids, oleic acid, palmitic acid, tocopherols, γ-tocopherol, β-sitosterol, α-, γ-and δ-tocopherols, δ-tocopherol, sesamin, sesamol, sesamolin. [53,106]According to recent research, sesame oil may alleviate the pain, and stiffness associated with osteoarthritis of the knee. [107,108]e fruit Ananas comosus, which contains the antioxidant bromelain, may be used to treat OA. [109] Pineapple (A. comosus) is a member of the Bromeliaceae family and its stem has a greater concentration of bromelain.Anti-inflammatory, anti-edematous, and antithrombotic properties of bromelain have been reported.

Rosmarinus officinalis (Lamiaceae)
Rosemary -Reduces pain and improves physical function in knee osteoarthritis patients Leaves Organic solvents [114]  However, more studies are needed to investigate the bromelain (Figure 3q) in OA treatment. [67,110]own as the leopard plant, Arnica montana is a member of the Asteraceae family, and its gel is used to treat OA pain.Its gel reduces pain and stiffness in OA patients when applied twice daily for three weeks.13] Traditionally, the herb rosemary, scientifically known as Rosmarinus officinalis, has been used to treat conditions including asthma, dysmenorrhea, and the discomfort associated with renal colic.Anti-inflammatory, antioxidant, and anti-nociceptive benefits are all attributed to Rosemary.Monoterpenes are the primary constituents of rosemary.In-vitro studies of rosemary reveal that its extract slows down the cartilage degeneration process and could be used for the treatment of OA.Also, the emulsion of peppermint essential oil and rosemary reduces OA joint pain, and improve histopathological features of rat joint. [114,115]NCLUSION Herbal drugs and their bioactive fractions are probably valuable for preventing or alleviating the pain and progression of OA.
A variety of civilizations across the world make use of herbal treatments for treating OA.Many herbal remedies have been developed as a result of research into the anti-osteoarthritic properties of herbal plants.A variety of data were obtained for this study, including information on the plant's potential, toxicity profile, mechanism of action, and the phytochemical responsible for anti-osteoarthritic efficacy.Finally, we can say that several of the plants included in Table 1 exhibit anti-osteoarthritic action that is promising.Inflammatory mediators are reduced in people with rheumatoid arthritis by certain plants, while others stop the destruction of cartilage.

Limitations and Future prospective
Several plants are reported which could be utilised in the treatment of OA as mentioned in the Table 1, but some traditional plants used in OA treatment are not experimentally proven in the OA treatment.Some plants showed anti-arthritic activity in the preclinical stage, but the clinical data is not available for those plants.Also, data for the active isolated phytochemical is not adequately available for the OA.Most of the plants used in OA reduce NSAID usage, i.e., reduce the inflammatory mediators and reduce pain associated with the OA, but then again do not work on the chondrocytes, or cartilage degradation.So, further research, and clinical trials are needed to determine the anti-osteoarthritic activity of less explored plants.
Several clinical studies showed the target is cartilage lesions with reduced pain and inflammation, but there are very few plants showing the improvement in cartilage.However, there are significantly fewer herbal or allopathic drugs that reverse, or stop osteoarthritis's progression in the long term.So, the primary future approach for osteoarthritis treatment is must be focused on regenerative, or pharmacological therapy for the joint.So, the modulation of the mechanoreceptive pathway is the foremost new opportunity for osteoarthritis study.Also, exploration of new herbal plants, and clinical studies are required for osteoarthritis treatment.