- An international research team has identified a new molecular pathway thought to cause gout and its progression to joint tissue erosion.
- Researchers believe that lubricin, a protein found in joint fluid, may serve as a new therapeutic target for the prevention and treatment of gout.
- The researchers made the discovery in part by studying a woman who had developed urate crystal deposits and joint erosion but did not show high blood urate levels.
Gout, a common form of inflammatory arthritis, can cause severe pain, swelling, and stiffness in the joints.
Plaguing mankind since ancient times, gout usually affects one joint at a time, often the joint at the base of the big toe.
The condition affects more than 3 million people in the United States, according to the American College of Rheumatology.
The disease is more common in men, postmenopausal women and people with kidney disease.
An international research team led by the University of California San Diego School of Medicine has identified a new molecular pathway that causes gout and its progression to joint tissue erosion.
The researchers published their
The body produces uric acid when it breaks down purines, which are found in the body, in meat and in some drinks.
Hyperuricemia, an elevated level of uric acid in the blood, can cause uric acid crystals to form in the joint, causing inflammation.
People with gout also often have high levels of uric acid in them
However, hyperuricemia does not always cause gout.
“There are factors far beyond having a high serum percentage that determine who gets gout and who doesn’t,” Dr. Robert Terkeltaub, a professor at the University of California, San Diego School of Medicine, chief of the section of rheumatology at the Health System San Diego Department of Veterans Affairs and senior author of the study, said Medical News Today.
In their paper, the researchers discuss their study of a 22-year-old woman with an unusual case of gout. She developed urate crystal deposits and had erosions in her joints, but did not show high levels of urate in her blood.
For their study, the researchers used
They also used quantitative proteomic methods, a technique that allows comprehensive protein analysis to identify a molecular pathway causing the patient’s condition.
They tested samples from the young woman, her parents and others unrelated to the case.
Ultimately, the researchers identified a molecular pathway that was disrupted in the young woman. Their findings focused on
The researchers identified multiple proteins that were lower in the woman’s joint fluid than in the joint fluid of either of her parents, and lower than the pooled scores of four healthy controls.
“We were looking for something that would be either decreased tenfold in the patient … relative to the mother or father and the control, or increased tenfold in the patient relative to the mother or father and the healthy control.” And we found about a dozen proteins that were significantly reduced in the patient, Terkeltaub said.
One of these proteins was lubricin. The researchers then studied 18 people with simple gout and uncontrolled hyperuricemia. Of these, five also had low levels of lubricin.
“It is not clear why uric acid is so enriched in the joint fluid of patients with gout compared to the blood, and we discovered a mechanism where the cells and lining of the joint actually respond to inflammation by increasing the production of uric acid in the joint, and lubricin inhibits this.” .. inhibits the ability of crystals to deposit, inhibits the ability of uric acid to rise in the joint itself, and has already been assessed to reduce the ability of crystals to stimulate cells. So this is a new pathway that probably helps in a major way to explain why some people get gout and most others don’t… and why gout progresses in some people to a disease that really damages the joints,” Terkeltaub said.
In another part of the study, the researchers used mice engineered to lack lubricin and mice with lubricin. They injected interleukin-1β, an inflammatory cytokine, into the rodents’ knee joints.
“In the mice that did not produce lubricin, there was an enrichment of the key enzyme that actually produces uric acid, xanthine oxidase, in cells called macrophages in the lining of the joints,” Terkeltaub explained.
The experiment suggests that lubricin suppresses the secretion of urate and xanthine oxidase from activated white blood cells and also blocks urate crystallization in the joint.
The study shows that lubricin may work as a biomarker for gout, said Dr. Pooja Paul Khanna, an associate professor in the department of internal medicine at the University of Michigan School of Medicine. MNT. She did not participate in the study.
“In mouse models, they’re seeing that even if you don’t have high uric acid, you’re seeing damage because of these little, you know, monosodium urate crystals that are already happening. “That’s the pathway we could block because we’ve identified lubricin as the cause,” Kanna said. “If the mice are deficient, which means [they] lack of lubricin, [monosodium urate] the crystals are more likely to lodge and damage this joint. right And the same needs to be further studied in humans.
Terkeltaub emphasized that the study shows that lubricin’s role goes beyond lubricating joint tissues.
“Lubricin is something that’s really involved in what we call uric acid homeostasis in the joint, and it also does a whole bunch of other things: inhibits the inflammation caused by the crystals and limits the formation of the crystals,” he said.
Whether or not a person who has hyperuricemia develops gout, Terkeltaub explained, can be affected by gene variants an individual has for lubricin and other molecules that control lubricin.
Dr. Theodore Fields, a rheumatologist at Weill Cornell Medicine and Hospital for Special Surgery in New York, who was not involved in the study, said MNT that this study illustrates more can be learned about the pathogenesis of gout.
“It makes perfect sense that factors such as lubricin deficiency play a role in some patients because we continue to have large gaps in our knowledge of why some patients get gout and others don’t, even if they both have the same serum urate level,” he said.
Terkeltaub plans to do future research investigating gout biomarkers and whether lubricin could work as a new therapeutic target for gout prevention and treatment.