Accelerating functional gene discovery in osteoarthritis

Nat Commun. 2021 Jan 20;12(1):467. doi: 10.1038/s41467-020-20761-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Osteoarthritis / pathology
  • Osteoarthritis / surgery
  • Paired Box Transcription Factors / genetics
  • Phenotype


  • Paired Box Transcription Factors
  • homeobox protein PITX1
  • Gonadotropin-Releasing Hormone
  • iodothyronine deiodinase type II
  • Iodide Peroxidase