RAGE mediated activation of NF-kB may explain the origin and perpetuation of pain in fibromyalgia.
This is an essential publication because it:
- Demonstrates excess NF-kB activation in muscles of fibromyalgia patients;
- Provides a possible explanation for connective tissue changes in fibromyalgia; and,
- Suggests one means by which local pain and inflammation might become self-perpetuating in fibromyalgia.
AGE and RAGE
AGEs are Advanced Glycation Endproducts.
Under certain conditions, sugars can bind with proteins or fats to create an AGE. The reaction forming an AGE can happen in food before it is eaten, or it can happen inside the body after sugar is consumed.
Fructose is said to form AGEs 10x more easily than glucose. So consuming a lot of high fructose corn syrup (e.g. as in soda) might not be a good thing – because AGEs are bad for us.
AGEs link with other AGEs, so when they are present in sufficient concentration in a tissue they can all link together – resulting in a ’stiffer’ and less functional tissue.
AGEs are also bad because they cause inflammation – by binding to a specific receptor on the cell surface.
A large body of evidence suggests that AGEs are an important cause of almost all diabetes complications. Diabetics have much higher levels of AGEs because excess blood sugar results in an excess of AGEs. That is one reason why it is important for diabetics to keep their blood sugar under control.
RAGE is the Receptor for Advanced Glycation Endproducts.
When the AGE binds to RAGE it results in activation of NF-kB.
Activation of NF-kB results in inflammation.
Activation of NF-kB also results in the production of more receptors – more RAGE.
So a self-perpetuating, vicious cycle can emerge. AGE binds to RAGE which results in more inflammation AND more RAGE – the additional RAGE then binds to more AGE leading to more NF-kB activation, more inflammation and more RAGE…
This is very bad.
Besides diabetes, other chronic, inflammatory conditions that have been linked to RAGE include atherosclerosis, congestive heart failure and Alzheimer’s disease.
RAGE is not generally thought to be significant in fibromyalgia, but the study summarized below suggests that it might be of importance.
In studying the muscle tissue of fibromyalgia patients it was found that the level of AGEs were increased, and that this increase was associated with collagen changes (AGE modified collagen,) NF-kB activation and, perhaps most significantly, with the presence of RAGE.
As noted above, by activating NF-kB, RAGE can initiate a vicious cycle of localized inflammation.
The authors suggest that AGEs found in excess in the muscle of fibromyalgia patients may impact the disease:
- By affecting collagen structure – thus affecting connective tissue changes; and,
- By activating NF-kB – thus resulting in self-sustaining, and ultimately spreading, pain and inflammation.
Inhibition of NF-kB might therefore be of substantial benefit in relieving the pain and inflammation of fibromyalgia.
The Publication:
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Scand J Rheumatol. 2005 Nov-Dec;34(6):460-3.
Detection of elevated N epsilon-carboxymethyllysine levels in muscular tissue and in serum of patients with fibromyalgia.
Rüster M, Franke S, Späth M, Pongratz DE, Stein G, Hein GE.
Department of Internal Medicine III, Friedrich-Schiller-University of Jena, Germany.
OBJECTIVES: To compare levels of CML, an AGE (advanced glycation end product) present in the muscle tissue and in the serum of patients with fibromyalgia (FM) vs. healthy controls.
METHODS: The serum levels of CML were measured in 41 patients with FM and 81 healthy controls. The presence of CML, nuclear factor kappa B (NF-kB), the AGE receptor (RAGE), collagen types I, II, VI, and CD68-positive monocytes/macrophages in muscle tissue of 14 patients with FM was investigated.
RESULTS: Patients with FM showed significantly increased serum levels of CML and more CML, activated NF-kB and CD68-positive monocytes/macrophages in the muscle. The collagens and CML were found together, suggesting that the AGE modifications were related to collagen. RAGE was absent in controls but a faint and patchy staining was seen in FM.
CONCLUSIONS: In the connective tissue of fibromyalgic muscles there was more activated NF-kB and more of the CML AGE. Higher CML levels were found in fibromyalgia patients. RAGE was only found in the muscle of fibromyalgia patients – it was not found in those who did not have fibromyalgia.
AGE modification of proteins causes reduced solubility and high resistance to proteolytic digestion of the altered proteins (e.g. AGE-modified collagens).
AGEs can stimulate different types of cells by activation of the transcription factor NF-kB, mediated by specific receptors of AGEs (e.g. RAGE) on the cell surface.
Both mechanisms may contribute to the development, perpetuation, and spreading of pain characteristic in FM patients.
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