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Accelerating functional gene discovery in osteoarthritis.
- Source :
-
Nature communications [Nat Commun] 2021 Jan 20; Vol. 12 (1), pp. 467. Date of Electronic Publication: 2021 Jan 20. - Publication Year :
- 2021
-
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.
- Subjects :
- Animals
Bone and Bones pathology
CRISPR-Cas Systems
Cartilage pathology
Clustered Regularly Interspaced Short Palindromic Repeats
Disease Models, Animal
Drug Discovery
Gene Editing
Gonadotropin-Releasing Hormone genetics
Iodide Peroxidase
Mice
Mice, Knockout
Osteoarthritis pathology
Osteoarthritis surgery
Paired Box Transcription Factors genetics
Phenotype
Iodothyronine Deiodinase Type II
Genetic Association Studies
Genetic Predisposition to Disease genetics
Osteoarthritis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33473114
- Full Text :
- https://doi.org/10.1038/s41467-020-20761-5