Many Americans think of gout as a disease from a bygone era, similar to rickets or scurvy. The condition typically afflicted the wealthy and royalty, including American historical figures such as Benjamin Franklin and Thomas Jefferson.
In fact, gout is one of the earliest known diseases, first identified by the ancient Egyptians around 2640 BC. But the disease is more prevalent 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 D-shaped crystals in and around the joints, usually starting from the foot. Crystal deposits lead to flare-ups of intense 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 main cause of gout, but surprisingly most people with high urate levels do not 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. Therefore, hyperuricemia shouldn’t be the only thing that stimulates 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 new therapeutic target for disease prevention and treatment.
The scientists wanted to explore the genetic factors that lead not to elevated levels of circulating urate, but specifically to urate production and crystal deposition in the 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 have high blood urate levels.
“This natural and highly unusual disorder has provided a unique opportunity to look at gouty arthritis from a different perspective and understand what molecular processes contribute to the disease independent of hyperuricemia,” said lead author Robert Terkeltaub, MD. Diego School. of Medicine and Section Chief of Rheumatology at 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 prevents urate from crystallizing in the body’s 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 hyperacemic patient develops gout may therefore be influenced by the genetic variants they have for lubricin and other molecules that control its production or breakdown in the joint.
“Our results show that lubrication may be a new biomarker for tracking the risk of developing gout in patients and that new drugs to maintain and increase lubrication 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 of the San Diego Veterans Health 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 at the University of Ottawa; Gregory D. Jay at Rhode Island Hospital; Marwa Qadri of Jazan University; Talia J. Dambruoso of Brown University; Tannin Schmidt of the University of Connecticut Health Center; Nicola Dalbet and Ashika Chhana at the University of Auckland; Jennifer Höglund of the University of Gothenburg; Nancy Maltez of the Ottawa Riverside Hospital; and Niclas G. Karlsson of Oslo Metropolitan University.
Source of the story:
Materials supplied by University of California-San Diego. Original written by Nicole Mlynaryk. Note: Content can be edited for style and length.
