Accelerating functional gene discovery in osteoarthritis.
Animals
Bone and Bones
/ pathology
CRISPR-Cas Systems
Cartilage
/ pathology
Clustered Regularly Interspaced Short Palindromic Repeats
Disease Models, Animal
Drug Discovery
Gene Editing
Genetic Association Studies
Genetic Predisposition to Disease
/ genetics
Gonadotropin-Releasing Hormone
/ genetics
Iodide Peroxidase
Mice
Mice, Knockout
Osteoarthritis
/ genetics
Paired Box Transcription Factors
/ genetics
Phenotype
Iodothyronine Deiodinase Type II
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 01 2021
20 01 2021
Historique:
received:
29
11
2019
accepted:
14
12
2020
entrez:
21
1
2021
pubmed:
22
1
2021
medline:
2
2
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33473114
doi: 10.1038/s41467-020-20761-5
pii: 10.1038/s41467-020-20761-5
pmc: PMC7817695
doi:
Substances chimiques
Paired Box Transcription Factors
0
homeobox protein PITX1
0
Gonadotropin-Releasing Hormone
33515-09-2
Iodide Peroxidase
EC 1.11.1.8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
467Subventions
Organisme : Wellcome Trust
ID : 110141/Z/15/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110140
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110141
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206194
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK077148
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK065055
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 098051
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 101123
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
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