Gout: The lack of a particular protein in the joint fluid could be a potential cause.

Gout is a prevalent type of inflammatory arthritis that results in severe discomfort, inflammation, and rigidity in the joints. This condition has plagued mankind for ages, and it usually impacts one joint at a time, frequently the joint situated at the base of the big toe.

Gout is more prevalent in men, women who have undergone menopause, and individuals with kidney problems.

An international research that was headed by the University of California San Diego School of Medicine, was carried out and the researchers discovered a new molecular pathway that causes gout and leads to the erosion of joint tissue. They published their findings in the Journal Arthritis & Rheumatology.

A case study on gout that is atypical in nature

Uric acid is produced by the body during the breakdown of purines, which are present in the body, in meat, and in some beverages. 

When there is an excess of uric acid in the blood, known as hyperuricemia, it can result in the formation of uric acid crystals within a joint, leading to inflammation. 

Although individuals with gout typically have high levels of uric acid in their joint fluid, not everyone with hyperuricemia develops gout. According to one study, up to 21% of the population may have asymptomatic hyperuricemia.

“There are factors well beyond having a high serum urate to determine who gets gout and 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) said.

Gout can be caused by a variety of factors working together

The researchers discussed their study of an uncommon case of gout in a 22-year-old woman in their paper. Although she had developed urate crystal deposits and experienced joint erosion, she did not have high levels of urate in her bloodstream.

In their investigation, the researchers utilized several techniques, including whole genome sequencing, RNA-sequencing, and quantitative proteomic methods to identify a molecular pathway responsible for the patient's condition. They tested specimens from the patient, her parents, and unrelated individuals.

Ultimately, the researchers identified a disrupted molecular pathway centered on lubricin, a protein that lubricates joints. They found numerous proteins in the woman's joint fluid to be significantly lower than in her parents or 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 stated.

Lubricin was one of those proteins, and its levels were found to be low in five out of 18 people with common gout and uncontrolled hyperuricemia.

“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.

Lubricin has an inhibitory effect on inflammation

In another part of the research, the researchers utilized mice that were genetically modified to lack lubricin, as well as mice with normal levels of lubricin. Subsequently, the researchers administered Interleukin-1β, an inflammatory cytokine, into the knee joints of both groups of mice.

Macrophages in the joint lining of mice lacking lubricin exhibited an increase in the concentration of xanthine oxidase, a crucial enzyme responsible for uric acid production.

According to the experiment, lubricin inhibits the release of urate and xanthine oxidase by activated white blood cells, as well as prevents urate from forming crystals in the joint.

According to Dr. Puja Paul Khanna (not a participant of the study), who is an associate professor in the department of Internal Medicine at the University of Michigan Medical School, The research findings shows that lubricin may serve as a potential biomarker for gout.

Terkeltaub explained that lubricin plays a crucial role in maintaining the balance of uric acid in the joints, preventing inflammation caused by crystals and restricting crystal formation. Additionally, he suggests that the likelihood of developing gout due to hyperuricemia may depend on an individual's genetic variations for lubricin and other molecules involved in its regulation. He intends to conduct further research to identify biomarkers for gout and investigate the potential of using lubricin as a new therapeutic target for preventing and treating gout.