Joint diseases from the perspective of epigenetics

The two most common joint diseases, arthrosis and arthritis, have one thing in common: genes play a major role in their development. However, it is not so much the presence or absence of certain genes in our DNA, but mainly the so-called epigenetic processes – that is, external influences that determine whether the genes in question are switched on or off. So let’s take a look together at the epigenetic reactions involved in the onset and development of arthritis and arthritis, and how we can influence them through lifestyle and dietary supplements.

Arthrosis

Osteoarthritis is clearly the most common joint disease, affecting up to one fifth of the population. In the first stages, the cartilage covering the contact surfaces of the bones in the joint loses its elasticity. The cartilage then gradually cracks and thins, and later bone growths, swelling, inflammation, impaired mobility and other tissues in the joint are affected: bones, ligaments and menisci. Osteoarthritis most commonly affects the large joints of the lower limbs, especially the knees and hips, and possibly the joints of the vertebrae.

Osteoarthritis is one of the so-called multifactorial diseases in which several different causes are involved. In the past, its development was blamed mainly on mechanical factors, i.e. overexertion during physical activities and obesity, while environmental, ageing and gender factors were also attributed a role. In recent years, however, several studies have also focused on molecular events within cartilage cells and have linked the development of the disorder to genetics and epigenetics (4, 6). In the field of genetics, for example, polymorphisms in the GDF5 and MCF2L genes have been linked to the risk of arthrosis. In the field of epigenetics, all three basic epigenetic processes, i.e. gene methylation, histone acetylation and RNA silencing, have a significant impact on the risk of arthrosis (1).

The process of methylation, which affects the biology of cartilage cells called chondrocytes, probably plays the biggest role. When scientists examined the DNA of damaged and undamaged areas of cartilage in people with mild and advanced arthritis, they found more than a thousand differences in the methylation of genes (2). Further research has revealed changes in the methylation of more than a third of the genes that increase susceptibility to arthritis in patients (3).

Another important role is played by so-called transcription factors. These are special proteins involved in the process of transcribing DNA into RNA (the first step in the process by which proteins are made in the body based on DNA). Abnormalities in transcription factors are a common feature of a number of diseases, including arthritis (5). The transcription factor NFAT1 appears to be crucial. Studies in mice have shown that when NFAT1 is disrupted, the skeleton develops normally but undergoes changes that are part of the development of arthrosis, such as increased production of inflammatory substances called cytokines and loss of type II collagen, followed by cartilage cell formation, destruction of the joint surface and other negative processes (5, 6).

Cytokines are also part of the complex epigenetic process of arthritis. These are small protein molecules that are mostly produced by immune cells. Their effect in rheumatoid arthritis is well documented (11), but significant variations in their production, caused by different methylation of the relevant genes, have also been observed in arthritis, where they cause intense inflammatory processes, especially in the later stages of the disease (7). Inflammatory interleukins also play a role. In particular, interleukin 6 (IL-6) has a devastating effect, reducing the production of type II collagen and thus contributing to the loss and reduction of articular cartilage elasticity, a fundamental manifestation of arthrosis (26).

Different patterns of gene methylation and histone acetylation have also been found in arthrosis sufferers in the region of genes that produce enzymes that cause degradation of collagen (the main building block of cartilage) and aggrecan, to which chondroitin sulfate binds as a substance that gives cartilage its elasticity (8, 12).

Rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the so-called autoimmune diseases in which immune cells attack the body’s own tissues – here it is specifically an attack on synovial tissue, i.e. the joint lining. It is manifested mainly by the development of inflammation and swelling, gradually leading to deformation and loss of function of many joint structures. All this is accompanied by severe pain, which greatly affects the life of the patient.

RA affects an estimated one percent of the population. Unlike arthritis, it usually affects small joints first (e.g. fingers) and only later the large ones.

The exact cause of RA is not yet fully understood. Genetic factors play a role, with a total of thirty sites in the human genome identified as risk factors for RA (16), yet their contribution to the disease is not significant – tracking of identical twins has shown a concordance of only 10% (some sources report up to 15%), with the remainder attributed to environmental and epigenetic factors, both of which overlap (9, 16). Many environmental and lifestyle factors have epigenetic effects, i.e. they influence the activity of individual genes in human DNA.

Several epigenetic mechanisms are involved in the development of RA. An important role is played by microRNAs, which are small ribonucleic acid molecules that do not code for anything but are involved in the transcription of individual genes. They can thus suppress the production of certain proteins, in particular signalling proteins and transcription factors, and thus shape the immune response at several levels. When certain microRNAs are disrupted, in particular miR-146a and miR-155, this leads to the production of inflammatory cytokines and thus contributes to the development of disease (10).

Alterations in the methylation patterns of certain genes are also involved in the development of RA, and interestingly, these changes vary according to the joints affected (15). For example, in general, reduced methylation of certain genes has been shown in joint cells called synovial fibroblasts (e.g., the promoter of the CXCL12 gene) in RA patients (17). Synovial fibroblasts play a crucial role in the development of RA, as they actively contribute to joint damage by secreting inflammatory cytokines, chemokines and enzymes that promote the destruction of many joint tissues. Many of the damaged genes also negatively affect the body’s overall immune response. In addition, synovial fibroblasts are highly resistant to apoptosis, a process of programmed cell death by which damaged cells commit a kind of “cell suicide” (18, 20).

People with RA have also been found to have different activity of genes that make the body produce enzymes that change the chromatin structure of certain immune cells – particularly B-cells and T-cells. These changes in turn affect the production of transcription factor kappa B (NF-κB), which in turn results in changes in the production of inflammatory cytokines (especially TNF-α and interleukins) as well as inflammatory enzymes such as cyclooxygenase 2 (COX 2). As a result, the inflammatory process is triggered (16, 19). In particular, the third of the three basic epigenetic reactions, histone acetylation, is involved in NF-κB formation (20).

Prostaglandins, particularly prostaglandin E2 (PGE2), are another key substance in the development of rheumatoid arthritis, triggering inflammatory processes in the joints. PGE2 is produced in the human body from arachidonic acid by the enzyme mPGES-1 (microsomal prostaglandin E synthase).

Rheumatoid arthritis is significantly aggravated by smoking and the reason is also due to epigenetics. Smoking causes extensive changes in gene methylation across the entire human genome (13), and this includes regions involved in RA (14). Smoking also increases oxidative stress, impairs the immune system and contributes to the inflammatory changes that accompany RA (14).

Useful dietary supplements

Due to the high contribution of epigenetic processes to the development of arthritis and arthritis, modification of all components of lifestyle that influence the intensity of epigenetic reactions can bring great relief. In particular, a healthy diet or regular exercise has a positive effect, whereas smoking and environmental pollution have a negative effect. In terms of nutrition, a high intake of antioxidants is important because free radicals are also highly involved in cartilage damage (26). Of the types of exercise, cyclic aerobic activities are the most suitable, as they not only have an epigenetic effect but also improve the nutrition of cartilage tissue, which does not have its own vascular supply (27).

Dietary supplements offer very effective help. Of course, those that supply the basic building blocks of articular cartilage (especially collagen) are suitable, but it is also advisable to combine them with herbs and nutrients with epigenetic action.

Boswellie

The plant, also known as saw palmetto, contains high concentrations of boswellic acids, which affect all three basic biochemical processes involved in arthritis and arthritis: gene methylation, histone acetylation and silencing by miRNAs (21). In doing so, they are very effective in regulating processes related to inflammation, be it the production of COX 2, inflammatory cytokines and prostaglandins type E. This is important not only in arthritis, but also in more advanced arthritis (22-24). In addition, they also have a direct effect on pain (25). In the case of arthritis, for example, there was a significant reduction in pain and swelling and an increase in mobility after only eight weeks of use in people with advanced arthritis (22).

Read more about boswellia here.

Curcumin

The active substance contained in the spice turmeric stands out for its anti-inflammatory action, which is comparable to that of non-steroidal antirheumatic drugs such as Aspirin or ibuprofen. In particular, it effectively reduces the production of the enzyme COX 2 or the transcription factor NF-κB (28), which is important for reducing the level of inflammatory processes in both arthritis and rheumatoid arthritis. In arthrosis, curcumin protects chondrocytes (i.e. cartilage cells) and restores type II collagen production due to its antioxidant and epigenetic effects (29).
However, curcumin should be used together with piperine, the active ingredient of black pepper, which increases its bioavailability up to 20-fold (30).

Read more about curcumin here.

Rosemary

Rosemary contains the three most important substances with epigenetic action: carnosol, carnosic acid and rosmarinic acid. The first two in particular have a significant positive effect on inflammatory processes, mainly by reducing the production of inflammatory prostaglandins of the E type (32). This is important both in arthritis and in advanced stages of arthrosis. In both diseases, rosemary’s strong antioxidant action also plays a positive role, protecting collagen molecules and other joint structures from free radical damage (33).

Read more about rosemary here.