Accelerating functional gene discovery in osteoarthritis
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Published version
Author(s)
Bassett, John
Williams, Graham R
Type
Journal Article
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. This expanding resource of mutant mice will accelerate
functional gene discovery in osteoarthritis and offer drug discovery opportunities for this
common, incapacitating chronic disease.
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. This expanding resource of mutant mice will accelerate
functional gene discovery in osteoarthritis and offer drug discovery opportunities for this
common, incapacitating chronic disease.
Date Issued
2021-01-20
Date Acceptance
2020-12-14
Citation
Nature Communications, 2021, 12 (467), pp.1-18
ISSN
2041-1723
Publisher
Nature Research
Start Page
1
End Page
18
Journal / Book Title
Nature Communications
Volume
12
Issue
467
Copyright Statement
© The Author(s) 2021. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Wellcome Trust
Commission of the European Communities
European Commission
Wellcome Trust
Identifier
https://www.nature.com/articles/s41467-020-20761-5
Grant Number
101123/Z/13/A
666869
THYRAGE-666869
110141/Z/15/Z
Subjects
Animals
Bone and Bones
CRISPR-Cas Systems
Cartilage
Clustered Regularly Interspaced Short Palindromic Repeats
Disease Models, Animal
Drug Discovery
Gene Editing
Genetic Association Studies
Genetic Predisposition to Disease
Gonadotropin-Releasing Hormone
Iodide Peroxidase
Mice
Mice, Knockout
Osteoarthritis
Paired Box Transcription Factors
Phenotype
Cartilage
Bone and Bones
Animals
Mice, Knockout
Mice
Osteoarthritis
Disease Models, Animal
Genetic Predisposition to Disease
Iodide Peroxidase
Phenotype
Paired Box Transcription Factors
Gonadotropin-Releasing Hormone
Drug Discovery
Genetic Association Studies
CRISPR-Cas Systems
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Editing
Publication Status
Published
Date Publish Online
2021-01-20