Many Americans think of gout as a disease from a bygone era, similar to rickets or scurvy. The condition commonly afflicted the wealthy and royalty, including American historical figures such as Benjamin Franklin and Thomas Jefferson.
Gout is in fact one of the earliest known diseases, first identified by the ancient Egyptians around 2640 B.C. But the disease is more prevalent now than ever, affecting more than 10 million people in the United States or about 5 percent of the adult population. .
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.
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 published online December 1, 2022 in 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, RNA sequencing, and quantitative proteomics methods, the researchers were able to identify an important disrupted molecular pathway in the patient centered around a significant decrease in lubricin. Mucinous protein provides essential lubrication and protection to joint tissues and regulates the function of a specific type of white blood cell that promotes joint inflammation.
Further experiments confirmed that under healthy conditions, lubricin suppresses the secretion of urate and xanthine oxidase (a urate-producing enzyme) by activated white blood cells, and also blocks urate crystallization in the joint. The researchers then evaluated several patients with the common form of gout and confirmed that they, too, had markedly reduced levels of lubricin.
The authors suggest that whether or not a patient with hyperacemia develops gout may therefore be influenced by the genetic variants they have for lubricin and other molecules that control its production or degradation in the joint.
“Our results show that lubricin may be a novel biomarker for tracking 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 .
Coauthors include: Leigh-Ana Rossitto, Ru LiuBryan, Majid Ghassemian, Anaamika Campeau, and David J. Gonzalez of UC San Diego; Marin Miner at Veterans Affairs San Diego Healthcare System; Khaled Elsaid and Sandy Elsayed at Chapman University; Amanda Phipps-Green, Tony R. Merriman and Murray Cadzow of the University of Otago; Jacob Karsh of the University of Ottawa; Gregory D. Jay at Rhode Island Hospital; Marwa Qadri of Jazan University; Talia J. Dambruoso at Brown University; Tannin Schmidt at the University of Connecticut Health Center; Nicola Dalbet and Ashika Chhana at the University of Auckland; Jennifer Höglund at the University of Gothenburg; Nancy Maltez of the Ottawa Riverside Hospital; and Niclas G. Karlsson at Oslo Metropolitan University.
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Materials provided by University of California – San Diego. Original written by Nicole Mlynaryk. Note: Content can be edited for style and length.