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Gout May Be Caused by Deficiency of a Protein Found in Joint Fluid

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03/30/2023
medicalnewstoday.com

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Scientists are looking into the causes of gout. Design by MNT; Photography by Hulton Archive/Getty Images & Solskin/Getty Images
  • An international research team identified a novel molecular pathway believed to cause gout and its progression to erosion of joint tissue.
  • Researchers believe lubricin, a protein found in joint fluid, may serve as a novel therapeutic target for prevention and treatment of gout.
  • Researchers made the discovery, in part, by studying a woman who had developed urate crystal deposits and joint erosion but did not show high urate levels in her blood.

Gout, a common form of inflammatory arthritis, can cause intense pain, swelling, and stiffness in the joints.

A torment on humanity since ancient times, gout typically affects one joint at a time, often the joint at the base of the big toe.

The condition impacts more than 3 million people in the United States, according to the American College of Rheumatology.

The affliction occurs more frequently in men, post-menopausal women, and people with kidney disease.

An international research team led by University of California San Diego School of Medicine, has identified a novel molecular pathway that causes gout and its progression to erosion of joint tissue.

The researchers published their findings in the journal Arthritis & Rheumatology.

The body makes uric acid when it breaks down purines, which are found in the body, in meat, and in some beverages.

Hyperuricemia, an elevated level of uric acid in the blood, can lead to the development of crystals of uric acid forming within a joint, which causes inflammation.

Individuals with gout also often have high levels of uric acid in their joint fluid.

However, hyperuricemia doesn’t always cause gout.

One study reported an estimate that as much as 21% of the population has asymptomatic hyperuricemia.

“There are factors well beyond having a high serum rate to determine who gets gout, who doesn’t get gout,” Dr, Robert Terkeltaub, a professor at the University of California San Diego School of Medicine, the section chief of rheumatology at the Veterans Affairs San Diego Healthcare System, and senior author of the study, told Medical News Today.

In their paper, the researchers discussed their study of a 22-year-old woman with an unusual case of gout. She had developed urate crystal deposits and had erosion in her joints but did not show high levels of urate in her blood.

For their study, researchers used whole genome sequencing, an analysis of the complete DNA make up of an organism, RNA-sequencing, a tool that provides a quantitative analysis of messenger RNA molecules in a biological sample.

They also utilized quantitative proteomic methods, a technique that allows for a comprehensive analysis of proteins, to identify a molecular pathway causing the patient’s condition.

They tested specimens from the young woman, her parents, and others not associated with the case.

Ultimately, researchers identified a molecular pathway that was disrupted in the young woman. Their findings centered on lubricin, a protein that lubricates joints.

Researchers identified numerous proteins that were lower in the woman’s joint fluid than the joint fluid of either of her parents and lower than pooled results from four healthy controls.

“We looked for something that would either be tenfold decreased in the patient… relative to the mother or father and the control or tenfold increased in the patient relative to the mother or the father and the healthy control. And we found about a dozen proteins that were markedly decreased in the patient, Terkeltaub said.

One of those proteins was lubricin. Researchers then looked at 18 people with common gout and uncontrolled hyperuricemia. Of those, five also had low levels of lubricin.

“it’s been unclear why uric acid is so enriched in the joint fluid in gout patients compared to blood and we found a mechanism whereby cells and the lining of the joint actually respond to inflammation by increasing the production of uric acid in the joint and lubricin inhibits that… inhibits the ability of the crystals to deposit, inhibits the ability of uric acid to get raised in the joint itself and was already appreciated to decrease the ability of the crystals to stimulate cells. So this is a novel 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 be a disease that really damages the joints,” Terkeltaub said.

In another part of the study, researchers used mice engineered to not have lubricin and mice with lubricin. They injected Interleukin-1β, an inflammatory cytokine, into the knee joints of the rodents.

“In the mice that didn’t make lubricin, there was an enrichment of the key enzyme that actually makes uric acid, xanthine oxidase, in the cells called macrophages in the joint lining,” Terkeltaub explained.

The experiment suggests lubricin suppresses the secretion of urate and xanthine oxidase by activated white blood cells, and also blocks urate from crystallizing in the joint.

The study indicates lubricin could work as a biomarker for gout, Dr. Puja Paul Khanna, an associate professor in the department of Internal Medicine at the University of Michigan Medical School, told MNT. She was not involved with the study.

“In the mouse models, they are seeing that even if you did not have a high level of uric acid, but you are seeing damage because of those tiny little, you know, monosodium urate crystals happening already. That’s the pathway that we could block because we’ve identified lubricin as the reason,” Khanna said. “If the mice are deficient, meaning [they] lack lubricin, the [monosodium urate] crystals have a higher likelihood of depositing themselves and damaging that joint. Right? And the same needs to be studied further in humans.”

Terkeltaub stressed that the study shows the role of lubricin goes beyond lubricating joint tissues.

“Lubricin is something that’s really involved in the what we call the homeostasis of uric acid in the joint and also does a whole bunch of other things: inhibits inflammation caused by the crystals and it limits the crystals from forming,” he said.

Whether or not a person who has hyperuricemia develops gout, Terkeltaub explained, may be influenced by gene variants that the 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, told 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 major knowledge gaps about why some patients get gout and some don’t, even if both have the same level of serum urate,” he said.

Terkeltaub plans to do future research exploring biomarkers for gout and looking at whether lubricin could work as a novel therapeutic target for the prevention and treatment of gout.

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Schedule17 Jun 2024