Gout is the most common form of inflammatory arthritis, in which urate (a byproduct of purine-rich foods like meat and alcohol) builds up in the body and forms needle-shaped crystals in and around the joints, usually starting in the foot. The crystal deposits lead to flares of severe pain, joint swelling and tenderness, and can progress to chronic joint damage that limits patients’ movement and quality of life.
Excess urate circulating in the blood has long been considered the major cause of gout, but counterintuitively, most people with high urate levels do not actually develop the disease. In fact, asymptomatic hyperuricemia is approximately four times more prevalent than gout. So what else could be causing the disease?
In a new study an international research team identified a novel 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 the prevention and treatment of the disease.
The scientists were interested in exploring the genetic factors. To do this, they studied a rare case of gout in which the patient had developed urate crystal deposits and erosion in her joints but did not show high levels of urate in her blood.
Using whole 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 activated 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.
Khaled Elsaid, Tony R. Merriman, Leigh‐Ana Rossitto, Ru Liu‐Bryan, Jacob Karsh, Amanda Phipps‐Green, Gregory D. Jay, Sandy Elsayed, Marwa Qadri, Marin Miner, Murray Cadzow, Talia J. Dambruoso, Tannin Schmidt, Nicola Dalbeth, Ashika Chhana, Jennifer Höglund, Majid Ghassemian, Anaamika Campeau, Nancy Maltez, Niclas G. Karlsson, David J. Gonzalez, Robert Terkeltaub. Amplification of inflammation by lubricin deficiency implicated in incident, erosive gout independent of hyperuricemia. Arthritis & Rheumatology, 2022; DOI: 10.1002/art.42413
University of California – San Diego. “Study finds novel treatment targets for gout.” ScienceDaily. ScienceDaily, 13 December 2022. <www.sciencedaily.com/releases/2022/12/221213121554.htm>.
Photo by Michal Parzuchowski