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Mouse models for human hyperuricaemia: a critical review

Abstract

Hyperuricaemia (increased serum urate concentration) occurs mainly in higher primates, including in humans, because of inactivation of the gene encoding uricase during primate evolution. Individuals with hyperuricaemia might develop gout — a painful inflammatory arthritis caused by monosodium urate crystal deposition in articular structures. Hyperuricaemia is also associated with common chronic diseases, including hypertension, chronic kidney disease, type 2 diabetes and cardiovascular disease. Many mouse models have been developed to investigate the causal mechanisms for hyperuricaemia. These models are highly diverse and can be divided into two broad categories: mice with genetic modifications (genetically induced models) and mice exposed to certain environmental factors (environmentally induced models; for example, pharmaceutical or dietary induction). This Review provides an overview of the mouse models of hyperuricaemia and the relevance of these models to human hyperuricaemia, with an emphasis on those models generated through genetic modifications. The challenges in developing and comparing mouse models of hyperuricaemia and future research directions are also outlined.

Key points

  • Hyperuricaemia occurs mainly in higher primates, including in humans, primarily owing to inactivation of the uricase gene during primate evolution, which resulted in subsequent evolution of human-specific physiology to tolerate this inactivation.

  • Mouse models of hyperuricaemia have been widely used to provide valuable insights into urate biology but do not yet reliably and consistently simulate the urate-mediated hyperuricaemia that occurs in humans.

  • Such models are potentially valuable resources for dissecting the mechanisms underlying hyperuricaemia as well as the progression from hyperuricaemia to gout and associated comorbidities.

  • A key challenge is to develop uricase-disabled model mice that can survive with increased urate levels and remain healthy and fertile.

  • Community-wide efforts are needed to reach consensus about the definition of hyperuricaemia in mice, to develop protocols for generating suitable models of hyperuricaemia and to adhere to a standard protocol for urate measurements.

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Fig. 1: Urate metabolism in mammals.
Fig. 2: Generation of mouse models of hyperuricaemia.

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Acknowledgements

The authors thank S. Robertson and the Clinical Genetics Group in the University of Otago, Dunedin, New Zealand, for their valuable discussions of this Review. J.L. is grateful for the support of the Departments of Women’s and Children’s Health, Biochemistry and Pathology, University of Otago. W.-H.W. is funded by Cure Kids NZ and the University of Otago.

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Nature Reviews Rheumatology thanks H. -K. Ea and F. Lioté for their contribution to the peer review of this work.

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J.L., C.L. and W.-H.W. researched data for the article. N.D., T.R.M. and W.-H.W. contributed to discussion of content. J.L., N.D., H.Y., T.R.M. and W.-H.W. contributed to writing the article, and all authors reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Tony R. Merriman or Wen-Hua Wei.

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Competing interests

N.D. declares that she has received research grant funding from Amgen and AstraZeneca; speaker fees from AbbVie, Janssen and Pfizer; and consulting fees from AstraZeneca, Horizon and Kowa. T.R.M. declares he has received research grant funding from Ardea Biosciences and Ironwood Pharmaceuticals and has received consulting fees from Ironwood Pharmaceuticals. The other authors declare that they have no competing interests.

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Glossary

Mendelian ratios

The expected ratios of genotypes at a locus observed in offspring under Mendel’s law of independent assortment; if one allele is embryonically lethal, the ratio will be skewed.

Mendelian randomization

The use of genetic variation in genes of known function to examine the causal effect of an exposure on disease in observational studies.

Pseudogenization

The process of generating a pseudogene, which is a gene that has DNA segments related to a real gene but has lost some or all functionality during evolution.

Congenic

A congenic mouse strain has a defined segment from a donor strain introduced into its genome.

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Lu, J., Dalbeth, N., Yin, H. et al. Mouse models for human hyperuricaemia: a critical review. Nat Rev Rheumatol 15, 413–426 (2019). https://doi.org/10.1038/s41584-019-0222-x

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