The Complex Pathogenic Relationship Between Osteoarthritis, Gout, and Urate

Considerable evidence links osteoarthritis and gout (the most common type of inflammatory arthritis), and both these conditions are commonly observed in the same patient. Gout is characterized by a high level of uric acid in the blood, or hyperuricemia, which has a distinct role in the pathogenesis of gout. With disease-modifying agents available to treat hyperuricemia and gout, but not osteoarthritis, understanding if urate has a similar role in the development of osteoarthritis could have valuable clinical implications.

Asymptomatic hyperuricemia is often considered a biochemical or metabolic condition, whereas the onset of gout represents the progression to an inflammatory disease. In this case, inflammation is typically a response to increased crystal deposition in the tissue, which is a feature further associated with cartilage damage in osteoarthritis.¹ However, whether or not gout predisposes an individual to osteoarthritis is still unclear.

Relationship Between Gout and Osteoarthritis: Beyond Causal

Gout and osteoarthritis share several risk factors like older age, obesity, and prior joint injury — they are also associated with calcium pyrophosphate crystal deposition — but the discrepant risk factors are also revealing. Men are more likely to develop gout, while women are more likely to develop osteoarthritis. Both gout and osteoarthritis are associated with genetic factors, but the latter relates to the genetics responsible for cartilage dysfunction and body mass index, and gout relates to the renal system’s inability to handle urate.¹

Osteoarthritis and gout have similarities in how the disease manifests, and they both share a proclivity for some joints, including fingers, toes, and knees. In fact, patients with osteoarthritis in their finger joints commonly experience gouty arthritis, which is often associated with an accumulation of monosodium urate crystals. The opposite is true too: in patients with gout, joint sites involved in prior gout flares were 7 to 8 times more likely to experience osteoarthritis vs joints without gout flare history.¹

Although the 2 conditions undeniably intersect, causality between osteoarthritis and gout is much harder to discern. In fact, some studies that have aimed to understand causality in the past have reported that these two conditions were risk factors for one another. Risk of developing osteoarthritis was higher among patients with gout than those without gout, and patients with gout were more likely to have a preceding diagnosis of osteoarthritis.¹

Interchangeable Roles of Inflammation and Crystal Deposition

In some cases, factors associated with 1 condition appear to influence the other condition. For example, inflammation is not a primary symptom of osteoarthritis, but osteoarthritis is associated with IL-1β genes that mediate the inflammatory response in gout.¹ On the other hand, monosodium urate crystal deposition visualized in radiographic images of osteoarthritic joints were 5 to 10 times more likely to reveal characteristic cartilage damage, which was not seen in gout.¹

These research observations could indicate that crystal deposition in both conditions is responsible for the tissue damage associated with osteoarthritis and the painful inflammation associated with gout. In addition, it could mean that IL-1β genes found in both osteoarthritis and gout may be linked to inflammatory pathways that are activated by either calcium pyrophosphate or monosodium urate crystals accumulation.

Associations Between Hyperuricemia and Osteoarthritis

Studies on hyperuricemia and osteoarthritis are limited and often do not differentiate between asymptomatic hyperuricemia and established gout, making it difficult to distinguish the effects of urate and inflammation on osteoarthritis, gout and hyperuricemia.

In one of the few studies that have indeed studied this link in detail, participants with gout had a greater prevalence of osteoarthritis than those with asymptomatic hyperuricemia, and the progression of hyperuricemia to gout seemed to have a dose-response effect on osteoarthritis risk. It was also seen that more severe osteoarthritis associated with hyperuricemia was observed in leaner participants; this suggests that while obesity is a risk factor for osteoarthritis, it may overpower the specific metabolic effect of hyperuricemia.¹

Furthermore, in studies that did not distinguish asymptomatic hyperuricemia and gout, monosodium urate crystal deposition captured in imaging tests was associated with a higher prevalence of osteoarthritis. Interestingly, this association was not specific to the site of the deposited urate. In a large, population-based study, the presence of osteophyte, which is characteristic of osteoarthritis, was associated with hyperuricemia in women, but not men, even after adjusting for factors such as BMI.¹

Osteoarthritis and Urate: A Shared Pathogenesis

Although the epidemiologic relationship between hyperuricemia and osteoarthritis seems to rely on shared risk factors, eg, obesity, there are a lot more coincidences revealed when digging into their respective pathophysiology. Unlike gout, osteoarthritis and hyperuricemia develop due to the contributions of biomechanical and metabolic factors,² which largely overlap and even create a feed-forward loop.

Osteoarthritis may promote local urate crystallization, which is exacerbated by hyperuricemia. Osteoarthritis is characterized by destructive changes to the soft tissues of the joint², and degraded cartilage surfaces providing the perfect scaffold upon which urate deposits and crystalizes.¹ Damaged cartilage releases a set of molecules (chondroitin sulfates) that further promote urate precipitation.¹ Even as the inflammatory response is mediated, elevated serum urate in the synovial fluid seems to modulate the process of monosodium urate crystal formation.³

Alternatively, monosodium urate crystal deposition in the cartilage can create local mechanical and/or inflammatory damage, promoting the development of osteoarthritis. In this scenario, urate plays a biochemical role in osteoarthritis pathophysiology, where chondrocytes exposed to higher concentrations of microcrystalline urate increase IL-1β expression along with additional enzymes that promote chondrocyte death. Urate is further generated by dying cells, which in high-enough concentrations promotes crystal deposition on the cartilage.¹

Interactions Between Urate and Osteoarthritis Reveal Potential for Treatment

The complex relationship between gout and osteoarthritis may be more accurately defined by the clinical overlap between osteoarthritis and hyperuricemia, in that the biochemical mechanisms of urate and inflammatory mediators are shared by both conditions. Although osteoarthritis was historically considered a disease of passive degeneration that was largely untreatable, the efficacy of urate-lowering therapies used to manage hyperuricemia and gouty arthritis may be indicated in the treatment of osteoarthritis.

Future studies and additional research on the intersection of osteoarthritis, hyperuricemia, and gout can yield further knowledge on the interactions of these conditions and reveal new mechanisms of treatment.

References

1. Neogi T, Krasnokutsky S, Pillinger MH. Urate and osteoarthritis: evidence for a reciprocal relationship [published online November 22, 2018]. Joint Bone Spine. doi:10.1016/j.jbspin.2018.11.002
2. Ma CA, Leung YY. Exploring the link between uric acid and osteoarthritis [published online December 13, 2017]. Front Med. doi:10.3389/fmed.2017.00225
3. Martillo MA, Nazzal L, Crittenden DB. The crystallization of monosodium urate. Curr Rheumatol Rep. 2014;16:400.