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Accelerating functional gene discovery in osteoarthritis

Abstract

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.

Type Journal
ISBN 2041-1723 (Electronic) 2041-1723 (Linking)
Authors Butterfield, N. C.; Curry, K. F.; Steinberg, J.; Dewhurst, H.; Komla-Ebri, D.; Mannan, N. S.; Adoum, A. T.; Leitch, V. D.; Logan, J. G.; Waung, J. A.; Ghirardello, E.; Southam, L.; Youlten, S. E.; Wilkinson, J. M.; McAninch, E. A.; Vancollie, V. E.; Kussy, F.; White, J. K.; Lelliott, C. J.; Adams, D. J.; Jacques, R.; Bianco, A. C.; Boyde, A.; Zeggini, E.; Croucher, P. I.; Williams, G. R.; Bassett, J. H. D.
Responsible Garvan Author Prof Peter Croucher
Publisher Name Nature Communications
Published Date 2021-01-20
Published Volume 12
Published Issue 1
Published Pages 467
Status Published in-print
DOI 10.1038/s41467-020-20761-5
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/33473114