The crystallization of monosodium urate

Abstract

Gout is a common crystal-induced arthritis, in which monosodium urate (MSU) crystals precipitate within joints and soft tissues and elicit an inflammatory response. The causes of elevated serum urate and the inflammatory pathways activated by MSU crystals have been well studied, but less is known about the processes leading to crystal formation and growth. Uric acid, the final product of purine metabolism, is a weak acid that circulates as the deprotonated urate anion under physiologic conditions, and combines with sodium ions to form MSU. MSU crystals are known to have a triclinic structure, in which stacked sheets of purine rings form the needle-shaped crystals that are observed microscopically. Exposed, charged crystal surfaces are thought to allow for interaction with phospholipid membranes and serum factors, playing a role in the crystal-mediated inflammatory response. While hyperuricemia is a clear risk factor for gout, local factors have been hypothesized to play a role in crystal formation, such as temperature, pH, mechanical stress, cartilage components, and other synovial and serum factors. Interestingly, several studies suggest that MSU crystals may drive the generation of crystal-specific antibodies that facilitate future MSU crystallization. Here, we review MSU crystal biology, including a discussion of crystal structure, effector function, and factors thought to play a role in crystal formation. We also briefly compare MSU biology to that of uric acid stones causing nephrolithasis, and consider the potential treatment implications of MSU crystal biology.

Figure 1

Physical chemistry of uric acid and monosodium urate formation. At physiologic pH of 7.4 and 37 °C, urate predominates. Urate can combine with sodium present in solution to form the less-soluble salt form, monosodium urate

Figure 2

Hypothetical model of the initiation and propagation of monosodium urate crystallization. A) Monosodium urate molecules remain fully in solution until an event that changes their solubility (e.g., increased concentration and decreased temperature, as discussed in the text). B) Soluble monosodium urate molecules begin to cluster while still in solution. C) Clusters aggregate into crystal nuclei, the basis for additional crystal formation and growth. D) Formation of fully-aggregated monosodium urate crystals. Top, monosodium urate in the crystals are arranged in flat sheets as seen in cross-section. Middle, the surface of these flat sheets forms the major growth faces of the crystal, with the flat sheets stacking along the crystal’s long axis. Bottom, fully formed (but potentially still growing) crystal, whose three axes are non-perpendicular (i.e., triclinic structure). Local factors may promote nucleation and/or crystal growth (e.g., pH and others; see text)