Scientists have discovered another possible reason why some people develop gout while others with similarly high uric acid levels do not.
Researchers led by the University of California San Diego found that low levels of a natural joint-protecting protein called lubricin may play an important role in the painful disease.
Gout is a common form of inflammatory arthritis. It develops when uric acid forms tiny needle-shaped crystals inside or around a joint, triggering sudden inflammation, swelling, redness and severe pain.
The first attack often occurs in the big toe, but gout can also affect the ankles, knees, wrists, fingers and other joints. Without effective treatment, repeated attacks can become more frequent and may eventually damage joints.
Uric acid is produced when the body breaks down substances called purines, which occur naturally in the body and are also found in some foods. The kidneys normally remove much of this uric acid through urine, but levels can rise when the body produces too much or the kidneys cannot remove enough.
For many years, high blood uric acid has been considered the main risk factor for gout. Yet it does not explain the whole story, because many people with high uric acid never develop the painful crystals that cause gout.
This mystery led researchers to investigate what else might determine whether crystals form inside a joint. Their new study points to lubricin, a protein found in the fluid surrounding joints.
Lubricin acts like a natural lubricant and protective coating. It reduces friction between joint surfaces and helps cartilage and other tissues move smoothly against one another during everyday activities.
The discovery began with an unusual patient who had serious gout and extensive deposits of uric acid crystals despite not having unusually high uric acid levels in her blood. Researchers examined her biology in detail to understand how gout could develop under these unusual circumstances.
They found major problems in biological pathways involved in joint health, including an unusually low amount of lubricin. This led the team to investigate whether the protein might do much more than simply help joints move smoothly.
Their experiments suggested that lubricin can make it harder for uric acid crystals to form in joint fluid. The protein also appears to influence inflammation and the activity of immune cells, both of which are important in determining how strongly the body reacts to uric acid crystals.
The researchers also found a possible connection between lubricin and xanthine oxidase, an enzyme involved in making uric acid. When lubricin levels are too low, conditions inside the joint may become more favorable for local uric acid production and crystal formation.
Importantly, the scientists did not see low lubricin only in the unusual patient. When they examined joint fluid from people with more typical gout, they also found reduced levels of the protein compared with what would normally be expected.
The findings could help explain why high blood uric acid alone does not determine who develops gout. Differences in genes and biological pathways that control lubricin may make the joints of some people more vulnerable to crystal formation than those of others.
Current gout treatments often focus on lowering uric acid throughout the body, and these medicines remain important for preventing attacks and long-term joint damage. The new research suggests that future treatments might also target conditions inside the joint itself, possibly by restoring lubricin or copying some of its protective effects.
However, researchers will need much more evidence before lubricin-based treatments can be used in patients. Scientists must determine exactly how the protein influences crystal formation and whether safely increasing its activity can prevent gout attacks.
The study was led by Robert Terkeltaub and colleagues and was published in the journal Arthritis & Rheumatology. The findings provide a new way to understand gout and may eventually help scientists develop treatments that protect joints as well as lower uric acid.
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