Study Identifies Novel Treatment Targets for Gout

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

UC San Diego researchers have developed a brand new mannequin of arthritis, specializing in the joint lubricating protein lubricin.

Many individuals view gout as a illness from the previous, just like rickets or scurvy. Traditionally, it affected rich and royal people, together with figures like Benjamin Franklin and Thomas Jefferson.

Nevertheless, it’s nonetheless a prevalent situation at the moment, affecting over 10 million individuals in the US, or roughly 5% of the grownup inhabitants. Regardless of its lengthy historical past, relationship again to historic Egypt, gout continues to be a major well being concern.

Gout is the commonest type of inflammatory arthritis, wherein urate (a byproduct of purine-rich meals like meat and alcohol) builds up within the physique and varieties needle-shaped crystals in and across the joints, normally beginning within the foot. The crystal deposits result in flares of extreme ache, joint swelling, and tenderness, and may progress to continual joint injury that limits sufferers’ motion and high quality of life.

A radiograph of the affected person’s foot revealed punched-out joint erosions within the large toe, options attribute of tophaceous, erosive gout. Credit score: UC San Diego Well being Sciences

Extra urate circulating within the blood (often called hyperuricemia) has lengthy been thought-about the key reason for gout, however counterintuitively, most individuals with excessive urate ranges don’t really develop the illness. In truth, asymptomatic hyperuricemia is roughly 4 occasions extra prevalent than gout. Gout sufferers additionally present mysteriously greater ranges of urate of their joint fluid in comparison with their blood. Thus hyperuricemia should not be the one factor stimulating urate crystal deposition within the joints. So what else may very well be inflicting the illness?

In a brand new examine lately printed within the journal Arthritis & Rheumatology, a global analysis staff led by the University of California San Diego School of Medicine recognized a novel molecular pathway that causes gout and its development to joint tissue erosion. The findings place lubricin, a protein present in joint fluid, as a novel therapeutic goal for each the prevention and remedy of the illness.

The scientists had been fascinated by exploring the genetic components that lead to not excessive ranges of circulating urate, however particularly to urate manufacturing and crystal deposition inside joints. To do that, they studied a uncommon case of gout wherein the affected person had developed urate crystal deposits and erosion in her joints however didn’t present excessive ranges of urate in her blood.

“This naturally occurring and very uncommon dysfunction supplied a singular alternative to have a look at gouty arthritis by a special lens, and perceive what molecular processes contribute to the illness unbiased of hyperuricemia,” stated senior creator Robert Terkeltaub, MD, professor at UC San Diego Faculty of Medication and part chief of Rheumatology on the Veterans Affairs San Diego Healthcare System.

Utilizing complete genome sequencing, 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.