Joints and articulations of our skeleton

To ensure its structure and mobility, our skeleton is made of several types of joints. We distinguish 3 different types of joints characterized by specific structures [1]:

• Fibrous joints (also called synarthroses) as in the skull: their structure is fixed and does not allow movement. The bony surfaces are bound by connective tissue and there is no cartilage in these joints.
• Cartilaginous joints (or amphiarthroses) such as vertebrae: their structure is semi-mobile and their bony surfaces are linked by a fibrous and fibrocartilaginous structure reinforced by ligaments.
• Synovial joints, which are called articulations: these joints, the most numerous in our skeleton, are characterized by an articular cavity and a synovial membrane. It is their anatomy, and precisely the presence of this cavity, that allows mobility.

Anatomy of the joints or synovial joints 

Joints are the most elaborate joints in the body, allowing a large range of motion. 

They are made up of several characteristic elements:

1. Joint surfaces with:

• The articular bone surfaces are covered with articular cartilage, called hyaline cartilage.
• Fibrocartilaginous surfaces interposed between bony surfaces such as the menisci in the knee joint cavity.

2. Joint mobility elements with:

• The joint capsule: this structure is composed of synovial and fibrous membranes. Richly vascularized and innervated, the synovial membrane of this capsule secretes the synovial fluid (or synovia), a viscous liquid that ensures the sliding between the two joined bone surfaces. 
• The ligaments: which give the joint its stability (completed by the periarticular muscles). 
• Tendons: bundles of fibers made of collagen, glycoproteins and proteoglycans that attach muscles to bones.

Representation of a synovial joint (from [1])

Among these structural elements, two are particularly interesting with their major compounds:

1. Cartilage:

Beyond skeletal mobility, the presence of cartilage (or cartilage tissue) on the bones gives our joints a shock absorbing role [2,3]. This tissue is composed of specific cells, the chondrocytes, which continuously produce the extracellular matrix of cartilage. This extracellular matrix brings together various compounds and structural molecules essential to cartilage. Various proteins are found in this articular cartilage matrix:

• Collagen: mainly type II (versus type I in the skin), 
• Glycosaminoglycans: mainly hyaluronic acid and chondroitin. 
• Proteoglycans: mainly aggregans, 
• Other proteins: "protein link", fibronectin...
• And small proteoglycans: biglycan, decorin and fibromodulin. 

This set gives the joint its compression capacity and resistance to the tensions exerted on the fabric.

2. Synovial membrane:

The synovial membrane (or synovium) of the joint capsule is made up of synoviocytes, the cells responsible for producing the hyaluronic acid contained in the synovial fluid. With its ability to retain up to 1,000 times its weight in water, hyaluronic acid helps to reduce friction and limit wear and tear on the joint, like a lubricant.

Joint problems

According to the WHO (World Health Organization), approximately 1.71 billion people worldwide suffer from osteoarticular and muscular diseases.

Among these conditions, osteoarthritis is defined as a degenerative process of chronic inflammation that affects the joints, mainly the knees, hands, shoulders, feet, and hips. 

The causes of osteoarthritis can be diverse: age, immunity, genetics, or mechanical causes such as obesity, intensive sports activity...

There are different forms of osteoarthritis, two of which are well known:

• Osteoarthritis: linked to an erosion of the joint, it is favored by natural aging and the phenomenon of inflammation. It is the most common joint pathology.  
• Rheumatoid arthritis: related to a dysfunction of the immune system, it results from an autoimmune disease.

In addition to these problems related to the joint structure, there are other problems such as tendonitis or tenosynovitis. These tendon affections result in pain that can be intense and cause real discomfort on a daily basis. Tendinitis is mainly caused by the repetition of movements and gestures that put excessive strain on the tendons.

Osteoarthritis 

Mainly related to aging, osteoarthritis is the most common joint disease. It is characterized by the destruction of cartilage and joint structure. 

Osteoarthritis represents a real public health issue because of the discomfort and pain it causes and the limitation of mobility it leads to on a daily basis. And because of the demographic growth and an increasingly long life expectancy, it is understandable that the number of people concerned is increasing. In France, 10 million people are affected by osteoarthritis, 65% of whom are over 65 years of age, and this number continues to increase [4].

At the physiological level, natural aging induces a progressive loss of cellular defenses throughout the body, and specifically in the joints. In addition, the production of specific inflammatory mediators at the joint level overactivates the immune system. These 2 factors (cellular senescence and the installation of inflammation) induce an environment conducive to the deterioration of joint structures with [5-7] :

• The degradation of the articular space and in particular that of the hyaline cartilage due to a lesser renewal of the hyaluronic acid of the synovial liquid.
• The formation of osteophytes, i.e. bone outgrowths induced by abnormal localized bone production.
• And bone remodeling around the joints. 

Osteoarthritis can occur acutely and chronically in all synovial joints of the body and to a greater extent in large joints such as the knees and hips. It is accompanied by pain and a loss of mobility that can be disabling. In the particular case of obesity, osteoarthritis is favored since the inflammation is already installed and the excess weight puts pressure on the joints [8].

Managing joint discomfort

The management of osteoarthritis generally involves a series of measures such as maintaining appropriate physical activity to avoid the negative spiral of immobility, but also taking care to limit inflammation and protect the joint. All of this helps to reduce the discomfort felt and limit joint disease.

The use of medications, such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs), helps to relieve the pain and sensations experienced in the joint. These solutions are used daily by more than half of the people who suffer from joint discomfort. In case of chronic inflammation and pain, other solutions can be used [9,10]. The scientific literature is relatively extensive in terms of active ingredients that have been clinically studied on the joint sphere, such as compounds present in the joint structure [11,12]:

• Collagen: abundant in the joint, collagen is particularly valued for its benefits on joint comfort as shown by numerous clinical studies.
• Hyaluronic acid: its intake has been studied (at doses lower than those of collagen, in the order of 200/60 mg over 1 to 3 months versus several grams for collagen) and shows that hyaluronic acid participates in chondroprotection, the protection of cartilage and the joint as a whole. It decreases the regulation of genes coding for joint inflammation mediators and acts locally on the global synthesis of glycosaminoglycans (the category of molecules to which it belongs) which directly improve the viscoelasticity of the joint affected by the inflammation [13-16]. 
• Chondroitin and glucosamine: often associated in joint formulas, they also appear in the literature [17,18]. Chondroitin is a glycosaminoglycan (the hyaluronic acid family) present in cartilage and synovial fluid that contributes to the viscosity of the joint. Taking chondroitin has shown positive effects on doses of 800 mg to 1200 mg per day over approximately 3 months. Mechanisms of action quite similar to those of hyaluronic acid have been described [19-22]. Glucosamine sulfate is one of the proteoglycans of cartilage. According to the literature, an average of 1.5 g per day over a period of 4 months would produce beneficial effects [23].

Comparison of the molecular structures of hyaluronic acid and chondroitin
It appears that the molecular size of hyaluronic acid is smaller than that of chondroitin, allowing it to be well absorbed by our body.

Besides these structural compounds, the literature also highlights the benefits of plants.

• Turmeric (Curcuma Longa): among the references, it is widely recognized by the scientific community and its effectiveness is no longer to be proven when the bioavailability of its compounds of interest is ensured. It has a global action on the inflammatory process which makes it an ingredient of choice to manage inflammation, without preventing wear and tear or acting specifically on inflammation in the joints.
• Harpagophytum (Harpagophytum procumbens, or devil's claw): if it benefits from interesting works on the articular sphere thanks to its richness in harpagosides, these data are relatively old compared to those of boswellia [13] with a dose of 50 to 60 mg of harpagosides per day minimum, over 4 weeks [14]. 
• Boswellia (Boswellia serrata): traditionally used for its soothing virtues, boswellia has been the subject of numerous clinical studies, notably at doses of 100 to 250 mg of extracts over periods of at least 4 weeks. Its benefits would result from boswellic acids, such as AKBA (the most powerful) showing a specific activity on joint inflammation: it inhibits 5-lipoxygenase, an enzyme involved in the inflammation process at the joint level. Specifically, this enzyme leads to the production of inflammatory mediators (leukotrienes) which are found in the synovial fluid and thus maintain an inflammatory phenomenon [15-18].

Finally, Methyl-Sulfonyl-Methane (MSM), a stable, natural source rich in sulfur, is also found in the literature. Nevertheless, few clinical studies (and not very recent) mention positive effects of this compound on the articular sphere. Moreover, the daily doses referenced are substantial, in the order of 3 g, and the associated results are measured approximately after 3 months of intake [19-21].

It is on the basis of this extensive literature highlighting ingredients of interest that we have selected active ingredients with targeted and complementary actions on joint discomfort.

The Nutri&Co formula: the daily solution to joint discomfort 

The development of our Joint Formula is based on the desire to offer a solution specifically adapted to joint comfort. It is a daily alternative to the traditional solutions to prevent the damage of the articulations in front of natural ageing while helping to fight against the inflammation.

For this, we have selected 3 complementary patented active ingredients for their benefits on :

• the inflammation process at the joint level,
• the structural components of the joint.

Boswellia and mangosteen to act on inflammation:

Our patented boswellia extract, Boswellin^®  Super (100mg) is derived from the resin of the Boswellia serrata tree. It is the extract, currently available, with the highest concentration of AKBA (30%), the boswellic acids of interest acting on the specific inflammation of the joint sphere [22,23]. It has several clinical studies demonstrating its effectiveness, tolerance and safety on joint comfort over several months.

To this boswellia extract, we have associated Mangoselect^® , a patented mangosteen extract. The active compounds of interest in this extract are alpha-mangostin (titrated to 10%) and gamma-mangostin (titrated to 1%), polyphenols that inhibit inflammatory stimuli (interleukins, pro-inflammatory molecules that activate the signals of these pathways).

A clinical study (in the course of publication) carried out on a dosage of 600 mg / day showed beneficial effects on the articular comfort in only 5 days in old subjects and sportsmen.

Hyaluronic acid, an essential joint structure compound:

We have selected a patented hyaluronic acid, ExceptionHYAL^®  Jump. Obtained by biotechnology, it is composed of a wide spectrum of hyaluronic acid molecules of low (2 KDa) and high (3000 KDa) molecular weight, giving it a profile identical in every way to endogenous hyaluronic acid and therefore easily usable by the body. 

Its efficacy, tolerance and safety have been clinically studied (under publication). A dose of 200 mg / day for 56 days by 60 subjects has demonstrated significantly positive effects from 28 days on the improvement of joint comfort. The results obtained show a faster action of this dosage compared to the smallest doses in the literature (30 mg). During this study, 70% of the subjects reduced their intake of usual solutions (versus 20% in the placebo).

References

1. Delmas, V. Système Articulaire. In PASS Anatomie Organisation des appareils et des systèmes; 2020.
2. Tamer, T.M. Hyaluronan and Synovial Joint: Function, Distribution and Healing. Interdiscip. Toxicol. 2013, 6, 111–125, doi:10.2478/intox-2013-0019.
3. Sophia Fox, A.J.; Bedi, A.; Rodeo, S.A. The Basic Science of Articular Cartilage: Structure, Composition, and Function. Sports Health Multidiscip. Approach 2009, 1, 461–468, doi:10.1177/1941738109350438.
4. INSERM Arthrose La Maladie Articulaire La plus Répandue Available online: https://www.inserm.fr/dossier/arthrose/#:~:text=un%20exc%C3%A8s%20de%20pression%20%3A%20une,contribuant%20%C3%A0%20ab%C3%AEmer%20le%20cartilage.
5. Lotz, M.K.; Caramés, B. Autophagy and Cartilage Homeostasis Mechanisms in Joint Health, Aging and OA. Nat. Rev. Rheumatol. 2011, 7, 579–587, doi:10.1038/nrrheum.2011.109.
6. Loeser, R.F. THE ROLE OF AGING IN THE DEVELOPMENT OF OSTEOARTHRITIS. 2017, 11.
7. Valdes, A.M.; Stocks, J. OSTEOARTHRITIS AND AGEING. 2017, 8.
8. Wluka, A.E.; Lombard, C.B.; Cicuttini, F.M. Tackling Obesity in Knee Osteoarthritis. Nat. Rev. Rheumatol. 2013, 9, 225–235, doi:10.1038/nrrheum.2012.224.
9. Heim, C.; Hügle, T. Douleurs et arthrose. Rev. Médicale Suisse 2018, 14, 1287–1290, doi:10.53738/REVMED.2018.14.612.1287.
10. HAS Questionnaire de Recueil Du Point de Vue Des Patients et Usagers Pour l’évaluation d’un Médicament - Evaluation de : HAPPYVISC®, Acide Hyaluronique Pour Injection Intra Articulaire; 2017;
11. Colletti, A.; Cicero, A.F.G. Nutraceutical Approach to Chronic Osteoarthritis: From Molecular Research to Clinical Evidence. Int. J. Mol. Sci. 2021, 22, 12920, doi:10.3390/ijms222312920.
12. Castrogiovanni, P.; Trovato, F.; Loreto, C.; Nsir, H.; Szychlinska, M.; Musumeci, G. Nutraceutical Supplements in the Management and Prevention of Osteoarthritis. Int. J. Mol. Sci. 2016, 17, 2042, doi:10.3390/ijms17122042.
13. Gagnier, J.J.; Chrubasik, S.; Manheimer, E. Harpgophytum Procumbens for Osteoarthritis and Low Back Pain: A Systematic Review. BMC Complement. Altern. Med. 2004, 4, 13, doi:10.1186/1472-6882-4-13.
14. Isaza, A. Nutraceuticals to Treat Joint Pain as An Alternative to Non-Steroidal Anti-. 2020, 4.
15. Abdel-Tawab, M.; Werz, O.; Schubert-Zsilavecz, M. Boswellia Serrata: An Overall Assessment of In Vitro, Preclinical, Pharmacokinetic and Clinical Data. Clin. Pharmacokinet. 2011, 50, 349–369, doi:10.2165/11586800-000000000-00000.
16. Alluri, V.K.; Kundimi, S.; Sengupta, K.; Golakoti, T.; Kilari, E.K. An Anti-Inflammatory Composition of Boswellia Serrata Resin Extracts Alleviates Pain and Protects Cartilage in Monoiodoacetate-Induced Osteoarthritis in Rats. Evid. Based Complement. Alternat. Med. 2020, 2020, 1–12, doi:10.1155/2020/7381625.
17. Brune, K. Safety of Anti-Inflammatory Treatment--New Ways of Thinking. Rheumatology 2004, 43, 16i–120, doi:10.1093/rheumatology/keh104.
18. Yu, G.; Xiang, W.; Zhang, T.; Zeng, L.; Yang, K.; Li, J. Effectiveness of Boswellia and Boswellia Extract for Osteoarthritis Patients: A Systematic Review and Meta-Analysis. BMC Complement. Med. Ther. 2020, 20, 225, doi:10.1186/s12906-020-02985-6.
19. Kim, L.S.; Axelrod, L.J.; Howard, P.; Buratovich, N.; Waters, R.F. Efficacy of Methylsulfonylmethane (MSM) in Osteoarthritis Pain of the Knee: A Pilot Clinical Trial. Osteoarthritis Cartilage 2006, 14, 286–294, doi:10.1016/j.joca.2005.10.003.
20. Butawan, M.; Benjamin, R.; Bloomer, R. Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement. Nutrients 2017, 9, 290, doi:10.3390/nu9030290.
21. Brien, S.; Prescott, P.; Bashir, N.; Lewith, H.; Lewith, G. Systematic Review of the Nutritional Supplements Dimethyl Sulfoxide (DMSO) and Methylsulfonylmethane (MSM) in the Treatment of Osteoarthritis. Osteoarthritis Cartilage 2008, 16, 1277–1288, doi:10.1016/j.joca.2008.03.002.
22. Majeed, M.; Vaidyanathan, P.; Natarajan, S.; Majeed, S.; Vuppala, K.K. EFFECT OF BOSWELLIN® SUPER ON KNEE PAIN IN JAPANESE ADULTS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL. 2016, 6.
23. Majeed, M.; Majeed, S.; Narayanan, N.K.; Nagabhushanam, K. A Pilot, Randomized, Double‐blind, Placebo‐controlled Trial to Assess the Safety and Efficacy of a Novel Boswellia serrata  Extract in the Management of Osteoarthritis of the Knee. Phytother. Res. 2019, 33, 1457–1468, doi:10.1002/ptr.6338.