Clearly, physicochemical factors play an important role, but other, less well-established factors must also be operative. Less is known about the critical intermediate step between hyperuricemia and the inflammatory Response-the process of MSU crystal formation. Interestingly, MSU crystals can persist in the joint fluid between attacks, suggesting that the inflammatory potential of MSU crystals may be modulated by synovial fluid elements. Upon infiltration, neutrophils are further activated by the crystals they encounter, producing additional pro-inflammatory mediators such as the arachidonic acid products PGE 2 and LTB 4. These mediators, along with complement directly activated at MSU crystal surfaces, initiate a neutrophilic influx that is the classic pathophysiologic feature of acute gout. Once formed, MSU crystals activate resident tissue macrophages, which secrete inflammatory cytokines including IL-1β. However, additional factors are required to push the individual over the threshold into hyperuricemia, including: renal underexcretion of urate conditions of excessive cell and purine turnover (e.g., leukemias, hemolytic anemias, etc.) high purine dietary intake and/or genetic factors that result in primary urate overproduction. The baseline risk factor for hyperuricemia, universal to humans as well as some other primates, is a series of mutational inactivations of the gene for the enzyme uricase, which in other mammals degrades urate to the more soluble molecule allantoin. The causes of hyperuricemia have been extensively studied, as have the mechanisms by which crystals initiate inflammation. Using this definition, hyperuricemia occurs at serum urate levels >6.8 mg/dL. Hyperuricemia is typically defined as occurring above the saturation point of MSU, at which point the risk of crystallization increases. The susceptibility to form MSU crystals is a consequence of excessive blood levels of soluble urate, one of the final products of the metabolic breakdown of purine nucleotides. In gout, deposition of monosodium urate (MSU) crystals within joints and connective tissue engenders highly inflammatory but localized responses. Gout is the most common arthropathy associated with crystal formation, and the most common inflammatory arthritis overall. We also briefly compare MSU biology to that of uric acid stones causing nephrolithasis, and consider the potential treatment implications of MSU crystal biology. Here, we review MSU crystal biology, including a discussion of crystal structure, effector function, and factors thought to play a role in crystal formation. Interestingly, several studies suggest that MSU crystals may drive the generation of crystal-specific antibodies that facilitate future MSU crystallization. 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. 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. 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. 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. 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. Gout is a common crystal-induced arthritis, in which monosodium urate (MSU) crystals precipitate within joints and soft tissues and elicit an inflammatory response.
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