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Nutrients for the joints: cartilage, tendons, ligaments, bones

Posted on by Swiss Alp Nutrition

Collagen I, II, III

Collagen is the most abundant protein in the human body and in mammals. It forms fibres in the extracellular matrix, giving shape and mechanical properties to tissues. There are 28 types of collagen in our body, of which the first 3 are the most abundant. Type I collagen is mainly present in tendons, skin, blood vessel walls, cornea, the organic part of bones and teeth, around muscle fibres and plays an important role in tissue repair. Type II collagen accounts for 50% of the proteins in our cartilage and is present in the eye (the vitreous humor). Type III collagen is also present in the walls of blood vessels, skin, intestines and uterus. It is less robust than type I collagen, but the two are often combined in these tissues.

The effectiveness of collagen peptides has been highlighted in cases of osteoarthritis. The scores WOMAC1 and VAS2 have decreased, demonstrating a reduction in pain, joint stiffness and improved motor skills. This leads to a better quality of life for the patients in their daily activities.3–5

Type II collagen peptides help reduce rheumatoid arthritis, an inflammatory disease in which the immune system attacks the joints, in particular because of the presence of collagen. When native type II collagen is taken orally, the immune cells become accustomed to it and the presence of collagen in the body become normal again (oral tolerance). In a randomized, double-blind trial involving 60 patients with severe, active rheumatoid arthritis, a decrease in the number of swollen joints and tender joints occurred in subjects fed chicken type II collagen for 3 months but not in those that received a placebo. Four patients in the collagen group had complete remission of the disease. 6,7

For people who occasionally experience pain during sports or daily mobility, collagen peptides improve the extension capacity of the joint (e.g. knee), reduce pain and increase exercise time before discomfort.8 The consumption of collagen peptides also strengthens the stability of the joints and reduces the risk of repeated injuries. In sports people, performance is also improved. 9

The benefits of collagen hydrolysates are also found in cases of osteoporosis, decreasing the presence of bone decomposition markers and increasing mineral density, as well as bone regeneration markers.10–12

Find out more about the benefits of collagen and how it works

Lysine, Threonine

Lysine and threonine are essential amino acids, which means that our body cannot produce them and therefore we must provide them through our nutrition.

Lysine increases the absorption of calcium in the intestines and limits its evacuation through the urine, which helps to maintain healthy bones. It also promotes healthy blood vessels and smooth muscles and limits calcium deposits in the vessels by helping the calcium to move from the vessels to the bones.13,14

In addition, lysine is one of the amino acids necessary for the synthesis and then for the proper function and structure of collagen because it acquires numerous enzymatic modifications (post-translational modifications) and in particular those allowing the links in and between collagen chains.15 Lysine also inhibits MPPs (matrix metalloproteases), the enzymes responsible for collagen degradation.16 

These properties make lysine a valuable ally in the healing of wounds, for example on the skin. For bone healing, lysine also accelerates healing by 2 weeks: it will activate the osteoblasts that ensure bone formation, increase calcium and collagen content, promote vascularisation and stimulate the secretion of growth factors and insulin (entry of glucose into cells).17,18

Threonine is also an essential amino acid brought by nutrition. It is very important for the good structure of our tissues, as it is the precursor of glycine, the main amino acid of collagen. Moreover, threonine incorporated in collagen plays an important role in the stability of collagen and the links between chains. Threonine is also present in elastin fibres. 19,20

Find out more about those amino acids

Glucosamine and chondroitin Sulphates

Glucosamine is a monosaccharide naturally present in our body. It is the precursor of several glycosaminoglycans such as hyaluronic acid, chondroitin or keratan sulphate, which make up aggrecans, very important constituents of the extracellular matrix. Chondroitin is the most abundant of those glycosaminoglycans in our cartilage. It enables water to be retained in the tissue and therefore maintains its osmotic pressure, elasticity and flexibility.

The benefits of taking glucosamine and chondroitin sulphates for osteoarthritis have been studied and debated for a long time because of the irregularity of the results and a sometimes high placebo effect. Nevertheless, most groups now agree on the usefulness of these supplements and their safety, as they are often better tolerated than some anti-inflammatory drugs.21 The GAIT study22 in 2006 showed in 1583 patients that taking glucosamine and chondroitin combined made it possible to reduce daily pain (OARSI-OMERACT score)23 of people suffering from moderate or severe osteoarthritis. Other studies have pointed out that the combination of glucosamine and chondroitin can reduce pain in the same way as taking a narcotic analgesic (2x 50mg of Tramadol)24 or a COX2 inhibiting non-steroidal anti-inflammatory drug (Celecoxib)25, and increase mobility of the joint (temporomandibular or knee). This combination was associated with an improvement in Lequesne score26, showing better functioning of the disabling joint, and in the WOMAC score1, highlighting a decrease in pain in daily life. It could also reduce swelling, effusion and stiffness of the joint when the osteoarthritis is not too advanced.27–31 By limiting the progression of the disease and its symptoms over the long term, taking chondroitin and glucosamine reduces the risk of total joint replacement.32 Symptom improvement can be even more effective when glucosamine and chondroitin are combined with a source of flavonoids,31 like rosehip.

Find out more about chondroitin and glucosamine

Hyaluronic acid (as sodium salt: sodium hyaluronate)

Hyaluronic acid is one of the major components in the extracellular matrix. It combines with chondroitin and keratin sulphates and intermingles with collagen fibres. It has excellent viscoelasticity and high water-retention capacities, allowing it to lubricate, absorb shocks, regulate the water balance and stabilise the structure of the joint.33

It also protects against inflammation and oxidative stress. When taken, it reduces the production of nitric oxide and free radicals and increases the synthesis of antioxidants, thus reducing oxidative stress.33,34 It also mitigates the production of pro-inflammatory mediators, such as cytokines, bradykinin and prostaglandin, to limit over-inflammation.33 In addition, by interacting with nerve endings (which become less sensitive and therefore transmit less pain), hyaluronic acid also has analgesic properties.35

The benefits of hyaluronic acid have been observed on the joints in general. It increases joint mobility and function, reduces stiffness and pain. In addition, it increases the endogenous synthesis of proteoglycans, collagen and hyaluronic acid by synoviocytes and chondrocytes (cells of the joint), increasing cartilage regeneration. It also inhibits osteoclasts, which resorb subchondral bone and weaken the joint. It will also increase the density and vitality of chondrocytes, the cartilage cells that produce the molecules necessary for healthy, functional cartilage. The proliferation of fibroblasts and keratinocytes, as well as the synthesis of collagen fibres will also be increased. The properties of hyaluronic acid are therefore very important for healing. In the case of osteoarthritis, the levels of inflammation and oxidation are high, increasing cell death and damaging cartilage, bone and synovial fluid. Taking hyaluronic acid restores the properties of the synovial fluid and the metabolism of the joint cells. Several studies have pointed out that increasing the amount of hyaluronic acid in the joint leads to improved joint function, and reduced pain and stiffness. This is reflected in a reduction in VAS, WOMAC and Lequesne scores, highlighting an improvement and slowing of disease progression.33,37–39

Find out more about hyaluronic acid

Methyl-sulphonyl-methane (MSM)

Thanks to its sulphur composition, MSM is an agent against inflammation and oxidative stress. It will, for example, desensitize the immune system, reduce inflammatory cytokines and inhibit vasodilatation in chronic inflammation. It has a strong antioxidant power, notably by stimulating reducing enzymes and inhibiting certain cellular processes involved in the generation of free radicals.40

Thanks to its anti-inflammatory action, in particular through the suppression of inflammatory cytokines (TNFα, IL-1β), MSM can protect the cartilage and synovial fluid, thus improving the condition of the joint. It can also reduce pain after sport.40,41

Several clinical studies on osteoarthritis have shown that taking MSM reduces pain, stiffness and swelling in the joint, leading to improved physical function and daily performance. This is reflected in improved VAS (Continuous Pain Scale), WOMAC (joint function and pain), SF36 (quality of life) and Lequesne Index (joint function) scores, as well as a possible reduction in the use of anti-inflammatory drugs. Its anti-inflammatory and analgesic properties therefore make it a valuable ally in improving the symptoms of osteoarthritis and the quality of daily life.40,42–46

Taking MSM is also beneficial in arthritis because it reduces inflammation by reducing the expression of cytokines, certain inflammatory cell processes, as well as the amount of other markers such as anti-cyclic citrullinated peptide 2 (anti-CCP2), C-reactive protein (CRP) and rheumatoid factor (RF).40,47

These effects seem to be potentiated by an association with collagen or chondroitin-glucosamine.

Find out more about MSM

Rosehip

Rosehip has very powerful antioxidant powers, thanks to a high concentration of flavonoids, and contains more vitamin C than citrus fruits. It also has a high concentration of folate, vitamins A, B3, D and E, carotenoids, beta sitosterol, malic acid, tannins, magnesium, zinc, copper, as well as specific galactolipids and fatty acids such as linoleic acid, making it a long-appreciated health asset.36

The strong antioxidant properties of rosehip, thanks to its high content of flavonoids and phenolic compounds, protect against oxidative stress and ensure good communication and adhesion between cells. By increasing the activity of antioxidant enzymes (such as superoxide dismutase and catalase) rosehip reduces the concentrations of free radicals (ROS) and nitrogen oxides (NO) which can damage tissues. Rosehip extracts also have strong anti-inflammatory properties. Thanks to their fatty acid content, they inhibit the COX 1 and 2 enzymes as well as the metabolism of arachidonic acid, which otherwise induce numerous inflammatory mediators. Its galactolipids also block the synthesis of cytokines, chemokines, inflammatory prostaglandins by immune cells, limit the migration (chemotaxis) of lymphocytes in the blood, and reduce the blood concentration of inflammatory C-reactive proteins (CRP). Some of these components can furthermore moderate NFκB, whose overactivation induces inflammation, immune deregulation and tissue destruction.36,48,49

Rosehip extracts, especially its galactolipids, have a protective effect on cartilage and chondrocytes. They reduce the expression of genes linked to inflammation (cytokines, NO, PGE2, chemokines, etc.), as well as catabolic genes that degrade the extracellular matrix, particularly those of collagen-cleaving MMPs and aggregases.36,50,51 Rosehip may also limit inflammation of the synovial fluid, which may be associated with greater risk of osteoarthritis.52

Several clinical studies (placebo/blind double blind) have shown that taking rosehip extracts for at least 3 months is useful for osteoarthritis. Indeed, it helps to reduce pain and stiffness in the joint, limiting the dose of anti-inflammatory drugs required. It also leads to an increase in physical function (WOMAC score)1, which underlines a decrease in the severity of the disease.48,53,54 Rosehip is also effective against chronic back pain. Its pain-relieving properties are even more appealing because, unlike non-steroidal anti-inflammatory drugs (NSAIDs), rosehip does not influence coagulation and has no negative side effects such as ulcers.36

In the case of rheumatoid arthritis, an autoimmune disease in which our immune system attacks our joints, tissue damage is linked to a large amount of free radicals and nitrogen oxides. The strong antioxidant powers of rosehip limit their production, protecting cells from DNA and mitochondrial damage and limiting cell death.36

At the bone level, the presence of a small amount of free radicals can be beneficial because it signals the presence of calcified tissue to be disintegrated or a wound to be healed. However, too much oxidative stress can be linked to an increase in the activity of osteoclasts (bone resorption) and proteins such as MMPs (collagen breakdown), which will damage the extracellular matrix and weaken the bone structure. This is particularly the case in osteoporosis. Rosehip extract, thanks to its antioxidant effects, helps to regulate this process and thus increase the mineral density of the bone. It will also stimulate the differentiation of osteoblasts (formation of bone tissue), as well as the synthesis of collagen.36

Find out more about rosehip

Vitamins C, E, B3, K2, D3

The health benefits of vitamin C are well established, as it supports almost all the functions of our body. In the joints, vitamin C is an important regulator of cartilage and bone metabolism, in particular by influencing the differentiation of chondrocytes (cartilage cells) and osteoblasts (cells that form bone tissue).55 A significant increase in the number of collagen fibres was also observed as well as an acceleration in the healing of fractures.56 Vitamin C is key to maintaining healthy joints and preventing osteoarthritis and inflammation. 57
In fact, taking vitamin C reduces cartilage loss and prevents the appearance of osteoarthritis by reducing inflammation, oxidative stress, cell death and the synthesis of collagen-degrading MMPs.58 More specifically, regular use of vitamin C could reduce the risk of developing osteoarthritis by 11% (but not really stop its progression)59 and limit damage to the spinal cord of the knee as well as the size of the bone plateau, which are important elements in joint pathologies.60 In addition, there is an association between vitamin C deficiency and acute and chronic musculoskeletal pain, whereas its supplementation could reduce it and improve the patient’s quality of life.61 Vitamin C therapy reduces pain and the use of painkillers in people with early osteoarthritis while increasing the quality of life for everyone.57 It is also useful for reducing pain (Complex Regional Pain Syndrome Type I) after a fracture62 and limits the drop in blood vitamin C observed after arthroplasty surgery and the risk of arthrosfibrosis.63 According to EFSA, it is necessary for the normal functioning of cartilage and bone and protects against oxidative stress.*

Although some results are conflicting regarding the properties of vitamin D to relieve the symptoms of osteoarthritis, vitamin D supplementation may have been associated with a significant slowing down of knee abnormalities (joint structure and cartilage composition).64 It has also increased the strength and performance of the affected joint as well as the overall quality of life. Inflammation and oxidative damage in these patients were also significantly reduced, improving protein and DNA function.65,66 On the contrary, a vitamin D deficiency seems to be a risk factor for osteoarthritis.65,67 In addition, taking vitamin D may limit pain, which can be exacerbated by a deficiency.68 Concerning rheumatoid arthritis, it seems that many patients have a vitamin D deficiency, which could be related to the severity of the disease.69,70 In addition, vitamin D supplementation may limit musculoskeletal pain and prevent osteoporosis for these patients.69 Indeed, vitamin D is an important mediator and is involved in the regulation of various (mostly adaptive) immune responses and inflammation, essential roles in autoimmune diseases such as arthritis.71 According to EFSA, it is necessary for the normal maintenance of bones and calcium levels, and together with calcium can reduce bone demineralisation leading to osteoporotic fractures.*

Vitamin E is a powerful antioxidant and anti-inflammatory. It can therefore mitigate oxidative stress, which is one of the mechanisms that can lead to and accentuate the biomolecular degeneration of the joint causing osteoarthritis.72,73 It can also limit inflammation in the synovial fluid and cartilage, as well as pain.74, 75  Studies have pointed out that people suffering from osteoarthritis are often deficient in vitamin E, whereas its supplementation may limit the risks and delay the progression of osteoarthritis, thanks to different mechanisms (antioxidants, hormonal, immune, vascular, maintaining skeletal muscles, regulating cellular metabolism…).72,76 Similarly, it can prevent joint destruction, particularly by calming inflammation, in models of rheumatoid arthritis.77 According to EFSA, it protects against oxidative stress.*

Vitamin K is involved in the mineralisation of bone and cartilage, as well as in the regulation of the genes of the articular cartilage matrix and certain enzymatic reactions.78 People who are deficient in vitamin K are at greater risk of damage to cartilage and subchondral bone, which can lead to osteoarthritis and other joint diseases,78–81 whereas an adequate daily intake would appear to be protective.82 For vitamin K deficient people with osteoarthritis, taking vitamin K benefits the joints.83 Also, the intake of enough combined vitamins K and D allows an increase in walking speed and the ease of getting up from a chair for people with knee osteoarthritis.84 Vitamin K is of course also essential for good bone health, affecting bone strength and metabolism, notably by promoting the activation of bone-forming cells (osteoblasts) and proteins that mineralise the extracellular bone matrix.85 In addition to its role in mineralization, vitamin K seems to have an anti-inflammatory action, very useful for many chronic diseases (cardiovascular, osteoarthritis, osteoporosis…).86,87 In particular, it could reduce the level of inflammatory CRP in patients with rheumatoid arthritis. A clinical study has highlighted the improvement of the disease (less inflammation and proteins destroying the extracellular matrix) after 3 months of vitamin K intake.88 According to EFSA, it is necessary for the normal maintenance of bones.*

Although little studied, B vitamins may also be involved in bone health. Vitamin B3, also known as niacin, is effective in reducing oxidative stress,89,90 often very present in skeletal diseases. It could therefore play a role in the symptoms of osteoarthritis, improving the condition of the joint.91,92

Minerals (zinc, manganese, copper, selenium, calcium)

Zinc is a powerful antioxidant and is involved in the proliferation of chondrocytes (cartilage cells). Thus, zinc supplementation could prevent the progression of osteoarthritis.93 Similarly, zinc deficiency appears to correlate with the inflammation and progression of rheumatoid arthritis94,95, while zinc supplementation may reduce pain, stiffness, swelling, inflammation and pain medication in patients with psoriatic arthritis.96 Zinc also seems to play an important role in preventing and even curing osteoporosis, as it stimulates bone mineralisation and bone formation by osteoblasts and inhibits bone resorption by osteoclasts.97,98 The recommended daily dose of zinc is 10mg/d. Too much zinc can cause nausea or headaches. According to the EFSA, it is necessary for the normal maintenance of bones and protects against oxidative stress.*

Manganese and copper are essential for bone metabolism as they are co-factors for several enzymes. Their supplementation increases the mineral density of the bones, making them valuable allies against osteoporosis.99,100 These minerals, particularly when combined with zinc, are very effective in limiting bone loss.98
Manganese can play an important role in the formation of cartilage and bone collagen and in the mineralisation of bone.  It is also present in several antioxidant enzymes, which help limit free radicals.101 These antioxidant properties are particularly important for limiting inflammation in rheumatoid arthritis: it can act on the enzymes that regulate the amount of nitric oxide, particularly in the synovial fluid.102 Manganese, especially when combined with glucosamine and chondroitin, seems to be effective in alleviating the symptoms of osteoarthritis,103 in particular by modulating the metabolism of cartilage and synovial fluid.104 Manganese is also involved in the proper functioning of the immune system, the regulation of blood sugar levels, digestion, reproduction, bone growth…101 According to EFSA, it is necessary for the normal maintenance of bones and the formation of connective tissue, and protects against oxidative stress.* 
Copper is equally important for bone strength and mineralization, and for the prevention of skeletal abnormalities and osteoporosis. In particular, it helps promote collagen chain bonding, limits free radicals by being a co-factor of antioxidant enzymes and directly inhibits bone resorption by osteoclasts.98 A copper deficiency can therefore lead to skeletal problems such as osteoporosis, as well as dermatological, immune and cardiovascular problems, but too much copper consumption has also been associated with a high risk of fractures.105 According to EFSA, it is necessary for the normal maintenance of connective tissue and protects against oxidative stress.*
Attention, harmful effects, especially neurological, can occur with a consumption of more than 11mg/day for manganese (2mg = ADI) and gastrointestinal with more than 10mg/day of copper (1mg = ADI).100

Calcium is the mineral known per excellence for the health of our bones and the maintenance of a good mineralization of the bone mass.98 Nevertheless, the experts stress the importance of combining it with vitamin D to increase bone mineral density and limit osteoporosis as well as certain fractures, although the results in the latter case are more mixed.106,107 Indeed, vitamin D regulates the intestinal absorption of calcium.108 Studies suggest that it is even more effective to take them with zinc, copper and manganese to increase bone health.98 Good calcium intake also seems to be correlated with a reduced risk of knee osteoarthritis,109 which could be explained by the inhibition of cartilage cell (chondrocyte) death by blocking inflammatory cell pathways (COX-2).110 According to the EFSA, it is necessary for the normal maintenance of bones and, combined with vitamin D, can reduce bone demineralisation leading to osteoporotic fractures.*
Nevertheless, taking too much calcium (above 1000mg/day in addition to that in a normal diet) can lead to cardiovascular, renal or gastrointestinal complications.111  

Selenium is an essential nutrient for selenoproteins, which function as antioxidants that regulate inflammation and influence bone metabolism (proliferation of osteoblasts and inhibition of bone-resorbing osteoclasts). 98,112 Good selenium intake was associated with good bone mineralisation.113,112 Its properties highlight how it could provide some protection against osteoarthritis, rheumatoid arthritis, osteoporosis and bone damage from oxidative stress.98,114 Concerning osteoarthritis, selenium combined with vitamins A, B2, B6, C and E would make it possible to limit the disease, in particular by reducing oxidative stress.115 One study pointed out that combining selenium with vitamins C and E would be even more effective in preventing bone damage leading to osteoporosis.116 On the contrary, a selenium deficiency increases bone resorption and decreases the volume and the mineral density of the bone. In this sense, people with selenium deficiency are more at risk of osteoporosis and osteoporotic fractures.98 Similarly, selenium deficiency has been correlated with the risk of rheumatoid arthritis, in which inflammation and oxidative stress play an important role.117 According to EFSA, it protects against oxidative stress.*
Selenium also has an important role in the proper functioning of the immune, musculoskeletal, nervous, endocrine, cardiovascular and reproductive systems.118 Selenium consumption in Europe is often too low,119 the recommended dose of selenium is around 55mg/day, but intakes above 400mg/day can be toxic.120

Plants : Gentian, edelweiss, melon

Alpine plants traditionally used for their health benefits, the properties of gentian and edelweiss are impressive.

Gentian has an analgesic effect which helps to reduce persistent inflammatory pain. It can in fact modulate the transmission of pain and reduce the expression of certain pain receptors in the brain. This effect on the central nervous system could be due to the different compounds that gentian contains (gentiopicrosides, swertiamarine, sweroside). Gentian may also improve endurance performance.121,122 It has traditionally been used to treat inflammation of the joints, particularly in rheumatoid arthritis. By inhibiting COX-2 and the secretion of inflammatory cytokines, it indeed appears to be efficient.123

Taking edelweiss orally can have many health benefits: it is anti-inflammatory, analgesic and antioxidant.124,125 Its anti-inflammatory power can be seen in particular with the reduction in the secretion of inflammatory cytokines and the inhibition of chemotaxis, i.e. the reduction in the accumulation of leukocytes (white blood cells) in the inflamed tissues.124,125

To find out more about gentian and edelweiss

The properties of the melon, even though it does not come from the Alps, are not to be neglected either. Indeed, it is rich in SOD, an antioxidant enzyme essential to our proper functioning. Swiss Alp Health uses a special extract, Extramel®, which is highly dosed in SOD. Several studies have highlighted the antioxidant and anti-inflammatory properties of melon, reducing the production of inflammatory cytokines and free radicals, as well as stimulating the production of the anti-inflammatory cytokine (IL-10) by macrophages.126 It is also useful for limiting mental and muscular fatigue and stress.127

Osteoarthritis is often associated with an increase in oxidative stress,128 as this can lead to different inflammatory responses, cartilage cell death, degradation of the extracellular matrix, dysfunction of the subchondral bone, increased pain etc.129,130 It has been shown that the genes producing SOD are poorly expressed in people with osteoarthritis131,132 but not in other people of the same age, which encourages the oral consumption of SOD,133,134 especially as the SOD properties of the melon are preserved during digestion.126 In rats, the ingestion of SOD can reduce pain, joint disturbances and the production of inflammatory cytokines and thus help to protect the cells of the articular cartilage.135 In horses, the ingestion of SOD can limit oxidation and inflammation in the joints, preserve the integrity of the cartilage and alleviate joint pain.136

Learn more about joint pain, osteoarthritis, muscles, manual therapies, inflammation or the benefits of sport.

 

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* EFSA : official health claims from the European Food Safety Authority. An EFSA health claim is a statement about a relationship between a food and health. The European Commission authorises various health claims as long as they are based on scientific evidence.

  1. WOMAC Osteoarthritis Index – Physiopedia. https://www.physio-pedia.com/WOMAC_Osteoarthritis_Index.
  2. Visual Analogue Scale – Physiopedia. https://www.physio-pedia.com/Visual_Analogue_Scale.
  3. Crowley, D. C. et al. Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: A clinical trial. International Journal of Medical Sciences 6, 312–321 (2009).
  4. Benito-Ruiz, P. et al. A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort. International journal of food sciences and nutrition 60 Suppl 2, 99–113 (2009).
  5. Bello, A. E. & Oesser, S. Collagen hydrolysate for the treatment of osteoarthritis and other joint disorders: a review of the literature. Current medical research and opinion 22, 2221–32 (2006).
  6. Trentham, D. E. et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science 261, 1727–1730 (1993).
  7. Bagchi, D. et al. Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a mechanistic exploration. International journal of clinical pharmacology research 22, 101–10 (2002).
  8. Lugo, J. P. et al. Undenatured type II collagen (UC-II®) for joint support: A randomized, double-blind, placebo-controlled study in healthy volunteers. Journal of the International Society of Sports Nutrition 10, (2013).
  9. Dressler, P. et al. Improvement of functional ankle properties following supplementation with specific collagen peptides in athletes with chronic ankle instability. Journal of Sports Science and Medicine 17, 298–304 (2018).
  10. Zhang, H. et al. Preventive effects of collagen Peptide from deer sinew on bone loss in ovariectomized rats. Evidence-based complementary and alternative medicine : eCAM 2014, 627285 (2014).
  11. Adam, M., Spacek, P., Hulejová, H., Galiánová, A. & Blahos, J. [Postmenopausal osteoporosis. Treatment with calcitonin and a diet rich in collagen proteins]. Casopis lekaru ceskych 135, 74–8 (1996).
  12. König, D., Oesser, S., Scharla, S., Zdzieblik, D. & Gollhofer, A. Specific Collagen Peptides Improve Bone Mineral Density and Bone Markers in Postmenopausal Women-A Randomized Controlled Study. Nutrients 10, (2018).
  13. Civitelli, R. et al. Dietary L-lysine and calcium metabolism in humans. Nutrition (Burbank, Los Angeles County, Calif.) 8, 400–405 (1992).
  14. Shimomura, A. et al. Dietary L-Lysine prevents arterial calcification in adenine-induced uremic rats. Journal of the American Society of Nephrology 25, 1954–1965 (2014).
  15. Yamauchi, M. & Sricholpech, M. Lysine post-translational modifications of collagen. Essays in Biochemistry 52, 113–133 (2012).
  16. Roomi, M. W., Ivanov, V., Kalinovsky, T., Niedzwiecki, A. & Rath, M. Inhibition of cell invasion and MMP production by a nutrient mixture in malignant liposarcoma cell line SW-872. Medical Oncology 24, 394–401 (2007).
  17. Fini, M. et al. [Role of lactose, arginine and lysine combination in fracture healing (an experimental study)]. Annali italiani di chirurgia 67, 77–82; discussion 82-3 (1996).
  18. Spallotta, F. et al. Enhancement of lysine acetylation accelerates wound repair. Communicative and Integrative Biology 6, (2013).
  19. Bird, M. I., Nunn, P. B. & Lord, L. A. J. Formation of glycine and aminoacetone from l-threonine by rat liver mitochondria. BBA – General Subjects 802, 229–236 (1984).
  20. Jiravanichanun, N., Mizuno, K., Peter Bächinger, H. & Okuyama, K. Threonine in Collagen Triple-helical Structure. Polymer Journal 38, 400–403 (2006).
  21. Jerosch, J. Effects of glucosamine and chondroitin sulfate on cartilage metabolism in OA: Outlook on other nutrient partners especially omega-3 fatty acids. International Journal of Rheumatology vol. 2011 (2011).
  22. Clegg, D. O. et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. New England Journal of Medicine 354, 795–808 (2006).
  23. Hawker, G. A. et al. Development and preliminary psychometric testing of a new OA pain measure : an OARSI/OMERACT initiative International Cartilage Repair Society. Osteoarthritis and Cartilage 16, 409–414 (2008).
  24. Damlar, İ., Esen, E. & Tatli, U. Effects of glucosamine-chondroitin combination on synovial fluid IL-1β, IL-6, TNF-α and PGE2 levels in internal derangements of temporomandibular joint. Medicina Oral, Patologia Oral y Cirugia Bucal 20, e278–e283 (2015).
  25. Hochberg, M. C. et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: A multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Annals of the Rheumatic Diseases 75, 37–44 (2016).
  26. Indices algo-fonctionnels de Lequesne. http://www.rhumatologie.asso.fr/03-Services/instruments-pratiques/Lequesne.html.
  27. Vangsness, C. T., Spiker, W. & Erickson, J. A Review of Evidence-Based Medicine for Glucosamine and Chondroitin Sulfate Use in Knee Osteoarthritis. Arthroscopy – Journal of Arthroscopic and Related Surgery vol. 25 86–94 (2009).
  28. Mazieres, B., Combe, B., Van, A. P., Tondut, J. & Grynfeltt, M. Chondroitin sulfate in osteoarthritis of the knee: A prospective, double blind, placebo controlled multicenter clinical study. Journal of Rheumatology 28, 173–181 (2001).
  29. Calamia, V. et al. Pharmacoproteomic study of the effects of chondroitin and glucosamine sulfate on human articular chondrocytes. Arthritis Research and Therapy 12, (2010).
  30. Herrero-Beaumont, G. et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: A randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis and Rheumatism 56, 555–567 (2007).
  31. Kanzaki, N. et al. Effect of a dietary supplement containing glucosamine hydrochloride, chondroitin sulfate and quercetin glycosides on symptomatic knee osteoarthritis: A randomized, double-blind, placebo-controlled study. Journal of the Science of Food and Agriculture 92, 862–869 (2012).
  32. Bruyere, O. et al. Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials. Osteoarthritis and Cartilage 16, 254–260 (2008).
  33. Gupta, R. C., Lall, R., Srivastava, A. & Sinha, A. Hyaluronic acid: Molecular mechanisms and therapeutic trajectory. Frontiers in Veterinary Science 6, (2019).
  34. Nelson, F. R. et al. The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatology International 35, 43–52 (2015).
  35. Moreland, L. W. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Research & Therapy 5, 54 (2003).
  36. The Royal Australian College of General Practionners. Rosehip – an evidence based herbal medicine for inflammation and arthritis.
  37. Tikiz, C., Ünlü, Z., Şener, A., Efe, M. & Tüzün, Ç. Comparison of the efficacy of lower and higher molecular weight viscosupplementation in the treatment of hip osteoarthritis. Clinical Rheumatology 24, 244–250 (2005).
  38. Gigis, I., Fotiadis, E., Nenopoulos, A., Tsitas, K. & Hatzokos, I. Comparison of two different molecular weight intra-articular injections of hyaluronic acid for the treatment of knee osteoarthritis. Hippokratia 20, 26–31 (2016).
  39. Tashiro, T. et al. Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: A double-blind, placebo-controlled study over a 12-month period. The Scientific World Journal 2012, (2012).
  40. Butawan, M., Benjamin, R. L. & Bloomer, R. J. Methylsulfonylmethane: Applications and safety of a novel dietary supplement. Nutrients vol. 9 (2017).
  41. Withee, E. D., Tippens, K. M., Dehen, R. & Hanes, D. Effects of MSM on exercise-induced muscle and joint pain: a pilot study. Journal of the International Society of Sports Nutrition 12, (2015).
  42. Lubis, A. M. T., Siagian, C., Wonggokusuma, E., Marsetyo, A. F. & Setyohadi, B. Comparison of Glucosamine-Chondroitin Sulfate with and without Methylsulfonylmethane in Grade I-II Knee Osteoarthritis: A Double Blind Randomized Controlled Trial. Acta medica Indonesiana 49, 105–111 (2017).
  43. Usha, P. R. & Naidu, M. U. R. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clinical Drug Investigation 24, 353–363 (2004).
  44. Debbi, E. M. et al. Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: A randomized controlled study. BMC Complementary and Alternative Medicine 11, (2011).
  45. Notarnicola, A. et al. Methylsulfonylmethane and boswellic acids versus glucosamine sulfate in the treatment of knee arthritis: Randomized trial. International Journal of Immunopathology and Pharmacology 29, 140–146 (2016).
  46. Kim, L. S., Axelrod, L. J., Howard, P., Buratovich, N. & Waters, D. R. F. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial 1,2. doi:10.1016/j.joca.2005.10.003.
  47. Arafa, N. M., Hamuda, H. M., Melek, S. T. & Darwish, S. K. The effectiveness of Echinacea extract or composite glucosamine, chondroitin and methyl sulfonyl methane supplements on acute and chronic rheumatoid arthritis rat model. Toxicology and Industrial Health 29, 187–201 (2013).
  48. Vaishya, R., Agarwal, A. K., Shah, A., Vijay, V. & Vaish, A. Current status of top 10 nutraceuticals used for Knee Osteoarthritis in India. Journal of Clinical Orthopaedics and Trauma vol. 9 338–348 (2018).
  49. Mármol, I., Sánchez-De-Diego, C., Jiménez-Moreno, N., Ancín-Azpilicueta, C. & Rodríguez-Yoldi, M. Therapeutic applications of rose hips from different Rosa species. International Journal of Molecular Sciences vol. 18 (2017).
  50. Schwager, J., Hoeller, U., Wolfram, S. & Richard, N. Rose hip and its constituent galactolipids confer cartilage protection by modulating cytokine, and chemokine expression. BMC Complementary and Alternative Medicine 11, 105 (2011).
  51. Kharazmi, A. & Winther, K. Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo. Inflammopharmacology 7, 377–86 (1999).
  52. Saaby, L., Moesby, L., Hansen, E. W. & Christensen, S. B. Isolation of immunomodulatory triterpene acids from a standardized rose hip powder (Rosa canina L.). Phytotherapy Research 25, 195–201 (2011).
  53. Winther, K., Apel, K. & Thamsborg, G. A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial. Scandinavian journal of rheumatology 34, 302–8.
  54. Crawford, C., Boyd, C., Berry, K. & Deuster, P. Dietary Ingredients Requiring Further Research Before Evidence-Based Recommendations Can Be Made for Their Use as an Approach to Mitigating Pain. Pain Medicine 20, 1619–1632 (2019).
  55. Lindsey, R. C., Cheng, S. & Mohan, S. Vitamin C effects on 5-hydroxymethylcytosine and gene expression in osteoblasts and chondrocytes: Potential involvement of PHD2. PLoS ONE 14, (2019).
  56. DePhillipo, N. N. et al. Efficacy of Vitamin C Supplementation on Collagen Synthesis and Oxidative Stress After Musculoskeletal Injuries: A Systematic Review. Orthopaedic Journal of Sports Medicine vol. 6 (2018).
  57. Ripani, U., Manzarbeitia-Arroba, P., Guijarro-Leo, S., Urrutia-Graña, J. & de Masi-De Luca, A. Vitamin C May Help to Reduce the Knee’s Arthritic Symptoms. Outcomes Assessment of Nutriceutical Therapy. Medical archives (Sarajevo, Bosnia and Herzegovina) 73, 173–177 (2019).
  58. Chiu, P. R. et al. Vitamin c protects chondrocytes against monosodium iodoacetate-induced osteoarthritis by multiple pathways. International Journal of Molecular Sciences 18, (2017).
  59. Peregoy, J. & Wilder, F. V. The effects of vitamin C supplementation on incident and progressive knee osteoarthritis: A longitudinal study. Public Health Nutrition 14, 709–715 (2011).
  60. Wang, Y. et al. Effect of antioxidants on knee cartilage and bone in healthy, middle-aged subjects: A cross-sectional study. Arthritis Research and Therapy 9, (2007).
  61. Carr, A. C. & McCall, C. The role of vitamin C in the treatment of pain: New insights. Journal of Translational Medicine vol. 15 (2017).
  62. Zollinger, P. E., Tuinebreijer, W. E., Breederveld, R. S. & Kreis, R. W. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. Journal of Bone and Joint Surgery – Series A 89, 1424–1431 (2007).
  63. Behrend, H. et al. Vitamin C demand is increased after total knee arthroplasty: a double-blind placebo-controlled-randomized study. Knee Surgery, Sports Traumatology, Arthroscopy 27, 1182–1188 (2019).
  64. Joseph, G. B. et al. Associations between Vitamin C and D Intake and Cartilage Composition and Knee Joint Morphology over 4 years: Data from the Osteoarthritis Initiative. Arthritis Care & Research (2019) doi:10.1002/acr.24021.
  65. Ravalli, S., Szychlinska, M. A., Leonardi, R. M. & Musumeci, G. Recently highlighted nutraceuticals for preventive management of osteoarthritis. World Journal of Orthopaedics vol. 9 255–261 (2018).
  66. Manoy, P. et al. Vitamin D supplementation improves quality of life and physical performance in osteoarthritis patients. Nutrients 9, (2017).
  67. Zhang, F. F. et al. Vitamin D deficiency is associated with progression of knee osteoarthritis. Journal of Nutrition 144, 2002–2008 (2014).
  68. Helde-Frankling, M. & Björkhem-Bergman, L. Vitamin D in pain management. International Journal of Molecular Sciences vol. 18 (2017).
  69. Kostoglou-Athanassiou, I., Athanassiou, P., Lyraki, A., Raftakis, I. & Antoniadis, C. Vitamin D and rheumatoid arthritis. Therapeutic Advances in Endocrinology and Metabolism 3, 181–187 (2012).
  70. Meena, N., Chawla, S. P. S., Garg, R., Batta, A. & Kaur, S. Assessment of Vitamin D in rheumatoid arthritis and its correlation with disease activity. Journal of Natural Science, Biology and Medicine 9, 54–58 (2018).
  71. Aslam, M. M., John, P., Bhatti, A., Jahangir, S. & Kamboh, M. I. Vitamin D as a Principal Factor in Mediating Rheumatoid Arthritis-Derived Immune Response. BioMed Research International vol. 2019 (2019).
  72. Chin, K. Y. & Ima-Nirwana, S. The role of vitamin E in preventing and treating osteoarthritis – A review of the current evidence. Frontiers in Pharmacology vol. 9 (2018).
  73. Bhattacharya, I., Saxena, R. & Gupta, V. Efficacy of vitamin E in knee osteoarthritis management of North Indian geriatric population. Therapeutic Advances in Musculoskeletal Disease 4, 11–19 (2012).
  74. Rhouma, M., el Warrak, A. de O., Troncy, E., Beaudry, F. & Chorfi, Y. Anti-inflammatory response of dietary vitamin E and its effects on pain and joint structures during early stages of surgically induced osteoarthritis in dogs. Canadian Journal of Veterinary Research 77, 191–198 (2013).
  75. Rhouma, M., de Oliveira El Warrak, A., Troncy, E., Beaudry, F. & Chorfi, Y. Anti-inflammatory response of dietary vitamin E and its effects on pain and joint structures during early stages of surgically induced osteoarthritis in dogs – PubMed. Can J Vet Res (2013).
  76. Li, X., Dong, Z., Zhang, F., Dong, J. & Zhang, Y. Vitamin E slows down the progression of osteoarthritis (Review). Experimental and Therapeutic Medicine vol. 12 18–22 (2016).
  77. de Bandt, M. et al. Vitamin E uncouples joint destruction and clinical inflammation in a transgenic mouse model of rheumatoid arthritis. Arthritis and Rheumatism 46, 522–532 (2002).
  78. Shea, M. K. et al. The association between vitamin K status and knee osteoarthritis features in older adults: The Health, Aging and Body Composition Study. Osteoarthritis and Cartilage 23, 370–378 (2015).
  79. Thomas, S., Browne, H., Mobasheri, A. & Rayman, M. P. What is the evidence for a role for diet and nutrition in osteoarthritis? Rheumatology (Oxford) (2018) doi:10.1093/rheumatology/key011.
  80. Misra, D. et al. Vitamin K deficiency is associated with incident knee osteoarthritis. American Journal of Medicine 126, 243–248 (2013).
  81. Ishii, Y. et al. Distribution of vitamin K2 in subchondral bone in osteoarthritic knee joints. Knee Surgery, Sports Traumatology, Arthroscopy 21, 1813–1818 (2013).
  82. Chin, K. Y. The relationship between vitamin k and osteoarthritis: A review of current evidence. Nutrients 12, (2020).
  83. Neogi, T., Felson, D. T., Sarno, R. & Booth, S. L. Vitamin K in hand osteoarthritis: Results from a randomised clinical trial. Annals of the Rheumatic Diseases 67, 1570–1573 (2008).
  84. Shea, M. K. et al. Association of Vitamin K Status Combined With Vitamin D Status and Lower-Extremity Function: A Prospective Analysis of Two Knee Osteoarthritis Cohorts. Arthritis Care and Research 70, 1150–1159 (2018).
  85. Akbari, S. & Rasouli-Ghahroudi, A. A. Vitamin K and Bone Metabolism: A Review of the Latest Evidence in Preclinical Studies. BioMed Research International 2018, (2018).
  86. Harshman, S. G. & Shea, M. K. The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis. Current Nutrition Reports vol. 5 90–98 (2016).
  87. Simes, D. C., Viegas, C. S. B., Araújo, N. & Marreiros, C. Vitamin K as a powerful micronutrient in aging and age-related diseases: Pros and cons from clinical studies. International Journal of Molecular Sciences vol. 20 (2019).
  88. Schwalfenberg, G. K. Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health. Journal of Nutrition and Metabolism vol. 2017 (2017).
  89. Hamoud, S. et al. Niacin administration significantly reduces oxidative stress in patients with hypercholesterolemia and low levels of high-density lipoprotein cholesterol. American Journal of the Medical Sciences 345, 195–199 (2013).
  90. Pereira, L. C. et al. Niacin prevents mitochondrial oxidative stress caused by sub-chronic exposure to methylmercury. Drug and Chemical Toxicology 43, 64–70 (2020).
  91. Jonas, W. B., Rapoza, C. P. & Blair, W. F. The effect of niacinamide on osteoarthritis: A pilot study. Inflammation Research 45, 330–334 (1996).
  92. McCarty, M. F. & Russell, A. L. Niacinamide therapy for osteoarthritis – Does it inhibit nitric oxide synthase induction by interleukin-1 in chondrocytes? Medical Hypotheses 53, 350–360 (1999).
  93. Huang, T. C. et al. Zinc protects articular chondrocytes through changes in Nrf2-mediated antioxidants, cytokines and matrix metalloproteinases. Nutrients 10, (2018).
  94. Mierzecki, A., Strecker, D. & Radomska, K. A pilot study on zinc levels in patients with rheumatoid arthritis. Biological Trace Element Research 143, 854–862 (2011).
  95. Balogh, Z. et al. Plasma zinc and its relationship to clinical symptoms and drug treatment in rheumatoid arthritis. Annals of the Rheumatic Diseases 39, 329–332 (1980).
  96. CLEMMENSEN, O. J. et al. Psoriatic arthritis treated with oral zinc sulphate. British Journal of Dermatology 103, 411–415 (1980).
  97. Yamaguchi, M. Role of nutritional zinc in the prevention of osteoporosis. Molecular and Cellular Biochemistry vol. 338 241–254 (2010).
  98. della Pepa, G. & Brandi, M. L. Microelements for bone boost: The last but not the least. Clinical Cases in Mineral and Bone Metabolism vol. 13 181–185 (2016).
  99. Saltman, P. D. & Strause, L. G. The role of trace minerals in osteoporosis. Journal of the American College of Nutrition 12, 384–389 (1993).
  100. Price, C. T., Langford, J. R. & Liporace, F. A. Essential Nutrients for Bone Health and a Review of their Availability in the Average North American Diet. The Open Orthopaedics Journal 6, 143–149 (2012).
  101. Aschner, M. & Erikson, K. Manganese. Advances in Nutrition 8, 520–521 (2017).
  102. Sarban, S., Isikan, U. E., Kocabey, Y. & Kocyigit, A. Relationship between synovial fluid and plasma manganese, arginase, and nitric oxide in patients with rheumatoid arthritis. Biological Trace Element Research 115, 97–106 (2007).
  103. Leffler, C. T., Philippi, A. F., Leffler, S. G., Mosure, J. C. & Kim, P. D. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study – PubMed. Mil. Med. (1999).
  104. Johnson, K. A., Hulse, D. A., Hart, R. C., Kochevar, D. & Chu, Q. Effects of an orally administered mixture of chondroitin sulfate, glucosamine hydrochloride and manganese ascorbate on synovial fluid chondroitin sulfate 3B3 and 7D4 epitope in a canine cruciate ligament transection model of osteoarthritis. Osteoarthritis and Cartilage 9, 14–21 (2001).
  105. Qu, X. et al. Serum copper levels are associated with bone mineral density and total fracture. Journal of Orthopaedic Translation 14, 34–44 (2018).
  106. Harvey, N. C. et al. The role of calcium supplementation in healthy musculoskeletal ageing: An expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF). Osteoporosis International vol. 28 447–462 (2017).
  107. Sunyecz, J. A. The use of calcium and vitamin D in the management of osteoporosis. Therapeutics and Clinical Risk Management vol. 4 827–836 (2008).
  108. National Research Council (US) Committee on Diet and Health. Osteoporosis. (1989).
  109. Li, H. et al. Serum Calcium Concentration Is Inversely Associated with Radiographic Knee Osteoarthritis. Medicine (United States) 95, (2016).
  110. Kang, S. J., Kim, J. W., Kim, K. Y., Ku, S. K. & Lee, Y. J. Protective effects of calcium gluconate on osteoarthritis induced by anterior cruciate ligament transection and partial medial meniscectomy in Sprague-Dawley rats. Journal of orthopaedic surgery and research 9, 14 (2014).
  111. Li, K. et al. The good, the bad, and the ugly of calcium supplementation: A review of calcium intake on human health. Clinical Interventions in Aging vol. 13 2443–2452 (2018).
  112. Zeng, H., Cao, J. J. & Combs, G. F. Selenium in bone health: Roles in antioxidant protection and cell proliferation. Nutrients vol. 5 97–110 (2013).
  113. Beukhof, C. M. et al. Selenium status is positively associated with bone mineral density in healthy aging European men. PLoS ONE 11, (2016).
  114. Wang, Y. et al. Association between dietary selenium intake and the prevalence of osteoporosis: A cross-sectional study. BMC Musculoskeletal Disorders 20, (2019).
  115. Kurz, B., Jost, B. & Schünke, M. Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR/1N mice. Osteoarthritis and Cartilage 10, 119–126 (2002).
  116. Turan, B., Can, B. & Delilbasi, E. Selenium combined with vitamin E and vitamin C restores structural alterations of bones in heparin-induced osteoporosis. Clinical Rheumatology 22, 432–436 (2003).
  117. Tarp, U., Overvad, K., Hansen, J. C. & Thorling, E. B. Low selenium level in severe rheumatoid arthritis. Scandinavian Journal of Rheumatology 14, 97–101 (1985).
  118. Shreenath, A. P. & Dooley, J. Selenium Deficiency. StatPearls (2020).
  119. Stoffaneller, R. & Morse, N. L. A review of dietary selenium intake and selenium status in Europe and the Middle East. Nutrients vol. 7 1494–1537 (2015).
  120. Öztürk, N., Başer, K. H. C., Aydin, S., Öztürk, Y. & Çaliş, I. Effects of Gentiana lutea ssp. symphyandra on the central nervous system in mice. Phytotherapy Research 16, 627–631 (2002).
  121. Jia, N. et al. Iridoid glycosides from the flowers of Gentiana macrophylla Pall. ameliorate collagen-induced arthritis in rats. Journal of Ethnopharmacology 189, 1–9 (2016).
  122. Mubashir, K., Ganai, B. A., Ghazanfar, K. & Akbar, S. Evaluation of Antiarthritic Potential of Methanolic Extract of Gentiana kurroo Royle. Arthritis 2014, (2014).
  123. Speroni, E. et al. In vivo efficacy of different extracts of Edelweiss (Leontopodium alpinum Cass.) in animal models. Journal of Ethnopharmacology 105, 421–426 (2006).
  124. Dobner, M. J., Schwaiger, S., Jenewein, I. H. & Stuppner, H. Antibacterial activity of Leontopodium alpinum (Edelweiss). Journal of Ethnopharmacology 89, 301–303 (2003).
  125. Daniela, L. et al. Anti-inflammatory effects of concentrated ethanol extracts of edelweiss (Leontopodium alpinum Cass.) callus cultures towards human keratinocytes and endothelial cells. Mediators of Inflammation 2012, (2012).
  126. Vouldoukis, I. et al. Antioxidant and anti-inflammatory properties of a Cucumis melo LC. extract rich in superoxide dismutase activity. Journal of Ethnopharmacology 94, 67–75 (2004).
  127. Carillon, J., Notin, C., Schmitt, K., Simoneau, G. & Lacan, D. Dietary supplementation with a Superoxide dismutase-melon concentrate reduces stress, physical and mental fatigue in healthy people: A randomised, double-blind, placebo-controlled trial. Nutrients 6, 2348–2359 (2014).
  128. Poulet, B. & Beier, F. Targeting oxidative stress to reduce osteoarthritis. Arthritis Research and Therapy vol. 18 (2016).
  129. Zahan, O. M., Serban, O., Gherman, C. & Fodor, D. The evaluation of oxidative stress in osteoarthritis. Medicine and Pharmacy Reports vol. 93 12–22 (2020).
  130. Ziskoven, C. et al. Oxidative stress in secondary osteoarthritis: from cartilage destruction to clinical presentation? Orthopedic Reviews 2, 23 (2010).
  131. Scott, J. L. et al. Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease. Annals of the Rheumatic Diseases 69, 1502–1510 (2010).
  132. Regan, E. et al. Extracellular superoxide dismutase and oxidant damage in osteoarthritis. Arthritis and Rheumatism 52, 3479–3491 (2005).
  133. Koike, M. et al. Superoxide dismutase activity is significantly lower in end-stage osteoarthritic cartilage than non-osteoarthritic cartilage. PLoS ONE 13, (2018).
  134. Paździor, M. et al. The oxidative stress in knee osteoarthritis patients. An attempt of evaluation of possible compensatory effects occurring in the disease development. Medicina (Lithuania) 55, (2019).
  135. di Cesare Mannelli, L. et al. Therapeutic effects of the superoxide dismutase mimetic compound MnII MeO2A on experimental articular pain in rats. Mediators of Inflammation 2013, (2013).
  136. Notin, C., Vallon, L., Desbordes, F. & Leleu, C. Oral supplementation with superoxide dismutase in Standardbred trotters in training: A double-blind placebo-controlled study. Equine Veterinary Journal 42, 375–381 (2010).