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
