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Mechanisms of crystal formation in gout—a structural approach

Nature Reviews Rheumatology volume 11, pages 725–730 (2015)Cite this article

Subjects

Key Points

  • Mechanisms of biomineralization—the physiological formation of mineral crystals to build structural tissues such as bone or mollusc shells—provide a framework for interpreting pathological crystal formation as occurs in gout

  • Crystal formation is more enery-efficient when it occurs on a complementary surface, particularly on the surface of another crystal, than in a supersaturated solution

  • Fibres found in synovial fluid show monosodium urate monohydrate (MSU) crystals deposit in an orderly way: crystals lie parallel to the fibres, forming transverse rows that follow the undulations of the fibres

  • In tophi, two forms of crystal formation occur: templated nucleation on tissue fibres and, probably later, secondary nucleation on previously formed crystals

  • Imaging findings suggest MSU crystal formation in tendons follows the direction of collagen fibres and probably occurs on them; moreover, entheses seem to support crystal deposit in tendons

Abstract

The mechanisms and sites of monosodium urate monohydrate (MSU) crystal deposition in gout have received little attention from the scientific community to date. Formalin fixation of tissues leads to the dissolution of MSU crystals, resulting in their absence from routinely processed pathological samples and hence neglect. However, modern imaging techniques—especially ultrasonography but also conventional CT and dual-energy CT—reveal that MSU crystals form at the cartilage surface as well as inside tendons and ligaments, often at insertion sites. Tophi comprise round white formations of different sizes surrounded by inflammatory tissue. Studies of fibres recovered from gouty synovial fluid indicate that these fibres are likely to be a primary site of crystal formation by templated nucleation, with crystals deposited parallel to the fibres forming transverse bands. In tophi, two areas can be distinguished: one where crystals are formed on cellular tissues and another consisting predominantly of crystals, where secondary nucleation seems to take place; this organization could explain how tophi can grow rapidly. From these observations based on a crystallographic approach, it seems that initial templated nucleation on structural fibres—probably collagen—followed at some sites by secondary nucleation could explain MSU crystal deposition in gout.

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Figure 1: The structure of an MSU crystal.
Figure 2: Ultrasonographic images of MSU crystal deposit in tendons.
Figure 3: Formations of MSU crystals in tophi.
Figure 4: Small fragments of tissue containing orderly crystal deposits found in synovial fluid samples from asymptomatic gouty joints.
Figure 5: Possible mechanisms of MSU crystal formation on cartilage tissue.
Figure 6: Area of a tophus where crystals appear on cellular tissues.
Figure 7: Tophus area predominantly containing crystals.

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Author information

Authors and Affiliations

  1. Department of Medicine, Rheumatology Section, Hospital General Universitario de Alicante, Universidad Miguel Hernández, Pintor Baeza 12, Alicante, 03010, Spain

    Eliseo Pascual & Mariano Andrés

  2. Department of Structural Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot, 7610001, Israel

    Lia Addadi

  3. Rheumatology Unit, Hospital General Universitario de Elda, Carretera Elda-Sax SN, Elda, 03600, Spain

    Francisca Sivera

Authors
  1. Eliseo Pascual
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  4. Francisca Sivera
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All authors researched data for article and made substantial contributions to discussion of content, writing and review/editing of manuscript before submission.

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Correspondence to Eliseo Pascual.

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Supplementary information

Supplementary Figure Legends (DOCX 23 kb)

Supplementary Figure 1a

Formalin-fixed histological section of a tophus, where MSU crystals have disappeared. (TIFF 1218 kb)

Supplementary Figure 1b

Formalin-fixed histological section of a tophus, where MSU crystals have disappeared. (TIFF 1531 kb)

Supplementary Figure 2

CT scan of an elbow of a patient with tophaceous gout showing opaque MSU deposits. (TIFF 971 kb)

Supplementary Figure 3

Inflammation surrounding an area predominantly containing MSU crystals in a tophus. (TIFF 2441 kb)

Supplementary Figure 4a

Spherulitic formations in synovial fluid and synthetically formed MSU crystals. (TIFF 1403 kb)

Supplementary Figure 4b

Spherulitic formations in synovial fluid and synthetically formed MSU crystals. (TIFF 3693 kb)

Supplementary Figure 4c

Spherulitic formations in synovial fluid and synthetically formed MSU crystals. (PDF 1703 kb)

Supplementary Figure 5

Parallel bands of crystals at a predominantly crystal-containing site of a tophus indicates that crystals at these sites crystals are oriented and organized (TIFF 4361 kb)

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Pascual, E., Addadi, L., Andrés, M. et al. Mechanisms of crystal formation in gout—a structural approach. Nat Rev Rheumatol 11, 725–730 (2015). https://doi.org/10.1038/nrrheum.2015.125

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