by Many Americans consider gout to be a bygone disease, similar to rickets or scurvy. The situation has often affected the wealthy and the royal family, including American historical figures such as Benjamin Franklin and Thomas Jefferson.
Gout is indeed one of the oldest known diseases and was first described by the ancient Egyptians around 2640 BC. But the disease is now more common 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-shaped crystals in and around the joints, often starting in the feet. Crystal deposits cause exacerbations of severe pain, joint swelling and tenderness and can progress to chronic joint damage that limits the patient’s mobility and quality of life.
Excess urate circulating in the blood (known as hyperuricemia) has long been considered the main cause of gout, but contrary to logic, most people with high urate levels do not actually develop the disease. In fact, asymptomatic hyperuricemia is about four times more common than gout. People with gout also show mysteriously higher levels of urate in their joint fluids compared to their blood. Therefore, hyperuricemia should not be the only thing that stimulates urate crystal deposition in the joints. So what else can cause the disease?
In a new study published online on December 1, 2022 Arthritis and RheumatologyAn 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 lubrisin, a protein found in joint fluid, as a new therapeutic target for both prevention and treatment of disease.
The scientists were interested in discovering the genetic factors that lead not to high circulating urate levels, but to urate production and crystal deposition, particularly in the joints. To do this, they studied a rare case of gout where the patient developed urate crystal deposits and erosions in his joints but did not show high urate levels in his blood.
“This naturally occurring and highly unusual disorder has provided a unique opportunity to look at gouty arthritis through a different lens and to understand what molecular processes contribute to the disease independently of hyperuricemia,” said senior author Robert Terkeltaub, professor at the UC San Diego School. Chief of the Division of Rheumatology at the Department of Medicine and Veterans Affairs San Diego Health System.
Using whole genome sequencing, RNA sequencing and quantitative proteomic methods, the researchers were able to identify an important molecular pathway that is disrupted in the patient, focusing on a significant reduction in lubrisin. Mucinous protein provides essential lubrication and protection to joint tissues and regulates the function of a particular 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 (a urate-producing enzyme) by active white blood cells, and also prevents urate from crystallizing in the joint. The researchers then evaluated several patients with the diffuse form of gout and confirmed that their lubrisin levels were also markedly reduced.
The authors suggest that whether a patient with hyperaemia will go on to develop gout may be influenced by what gene variants they have for lubrisin and other molecules that control its production or destruction in the joint.
“Our findings suggest that lubricin could be a new biomarker for monitoring patients’ risk of developing gout, and that new drugs to protect and increase lubricin could limit the incidence and progression of gouty arthritis,” said Terkeltaub.
Co-authors are 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 of Rhode Island Hospital; Marwa Qadri at Jazan University; Talia J. Dambruoso of Brown University; Tannin Schmidt of the University of Connecticut Health Center; Nicola Dalbet and Ashika Chhana of the University of Auckland; Jennifer Höglund of the University of Gothenburg; Nancy Maltez at Ottawa Riverside Hospital; and Niclas G. Karlsson of Oslo Metropolitan University.
Story Source:
materials provided by University of California – San Diego. Originally written by Nicole Mlynaryk. Note: Content can be edited for style and length.
