Study identifies new therapeutic targets for gout

The painting of gout

James Gillray’s 1799 painting illustrates the painful symptoms of gout. Credit: Wellcome Library, London / CC By 4.0

Researchers at UC San Diego have developed a new model of arthritis, focusing on the joint lubricating protein lubricin.

Many people see gout as a disease of the past, similar to rickets or scurvy. Historically, it has affected wealthy and royal individuals, including figures such as Benjamin Franklin and Thomas Jefferson.

However, it is still a prevalent condition today, affecting over 10 million people in the United States, or about 5 percent of the adult population. Despite its long history dating back to ancient Egypt, gout continues to be a significant health problem.

Gout is the most common form of inflammatory arthritis, in which urate (a byproduct of purine-rich foods such as meat and alcohol) builds up in the body and forms needle-like crystals in and around the joints, usually starting in the foot. Crystal deposits lead to flare-ups of severe pain, joint swelling and tenderness and can progress to chronic joint damage that limits movement and patients’ quality of life.

Foot Patient With Gout

An X-ray of the patient’s foot revealed punctured joint erosions in the big toe, characteristic features of tophaceous and erosive gout. Credit: UC San Diego Health Sciences

Excess circulating urate in the blood (known as hyperuricemia) has long been thought to be the primary cause of gout, but counterintuitively, most people with high urate levels don’t actually develop the disease. In fact, asymptomatic hyperuricemia is about four times more common than gout. Gout patients also show mysteriously higher levels of urate in joint fluid than in blood. So hyperuricemia need not be the only thing stimulating the deposition of urate crystals in the joints. So what else could cause the disease?

In a new study recently published in the journal Arthritis and rheumatology, 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 findings position lubricin, a protein found in joint fluid, as a novel therapeutic target for both disease prevention and treatment.

Scientists were interested in exploring the genetic factors that lead not to elevated levels of circulating urate, but specifically to urate production and crystal deposition within joints. To do this, they studied a rare case of gout in which the patient had developed urate crystal deposits and erosion in the joints, but she did not show high blood urate levels.

“This natural and highly unusual disorder has provided a unique opportunity to look at gouty arthritis through a different lens and understand which molecular processes contribute to the disease independent of hyperuricemia,” said senior author Robert Terkeltaub, MD, professor at the UC San Diego School of Medicine and Section Chief of Rheumatology at the Veterans Affairs San Diego Healthcare System.

Using whole genome sequencing,[{” attribute=””>RNA-sequencing, and quantitative proteomic methods, the researchers were able to identify a major molecular pathway that was disrupted in the patient, centering on a significant reduction in lubricin. The mucinous protein provides essential lubrication and protection to joint tissues and regulates the function of a specific type of white blood cell that promotes inflammation in the joint.

Additional experiments confirmed that under healthy conditions, lubricin suppresses the secretion of urate and xanthine oxidase (an enzyme that produces urate) by activating white blood cells, and also blocks urate from crystallizing in the joint. The researchers then assessed several patients with the common form of gout and confirmed that they too had markedly decreased levels of lubricin.

The authors suggest that whether or not a hyperuricemia patient goes on to develop gout may thus be influenced by which gene variants they have for lubricin and other molecules that control its production or degradation in the joint.

“Our findings show that lubricin may be a new biomarker for tracing patients’ risk of developing gout and that new drugs to maintain and increase lubricin could limit the incidence and progression of gouty arthritis,” said Terkeltaub.

Reference: “Amplification of inflammation by lubricin deficiency implicated in incident, erosive gout independent of hyperuricemia” by Khaled Elsaid, Ph.D., Tony R. Merriman, Ph.D., Leigh-Ana Rossitto, BSc, Ru Liu-Bryan, Ph.D., Jacob Karsh, MD, Amanda Phipps-Green, MSc, Gregory D. Jay, MD, Ph.D., Sandy Elsayed, MSc, Marwa Qadri, Ph.D., Marin Miner, BSc, Murray Cadzow, Ph.D., Talia J. Dambruoso, MSc, Tannin Schmidt, Ph.D., Nicola Dalbeth, MD, FRACP, Ashika Chhana, Ph.D., Jennifer Höglund, BSc, Majid Ghassemian, Ph.D., Anaamika Campeau, Ph.D., Nancy Maltez, MD, Niclas G. Karlsson, Ph.D., David J. Gonzalez, Ph.D. and Robert Terkeltaub, MD, 1 December 2022, Arthritis & Rheumatology.
DOI: 10.1002/art.42413

The study was funded by the National Institutes of Health, the VA Research Service, the Health Research Council of New Zealand, the Rheumatology Research Foundation Innovation Research Award, the Royal Society of New Zealand Rutherford Foundation Post-Doctoral Research Fellowship, the Swedish state under the agreement between the Swedish government and the county council, the ALF-agreement, the Swedish Research Council, the Petrus and Augusta Hedlunds Foundation, the AFA Insurance Research Fund, and the UCSD Collaborative Center of Multiplexed Proteomics. 

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