TY - JOUR
T1 - Accelerating functional gene discovery in osteoarthritis
AU - Butterfield, Natalie C.
AU - Curry, Katherine F.
AU - Steinberg, Julia
AU - Dewhurst, Hannah
AU - Komla-Ebri, Davide
AU - Mannan, Naila S.
AU - Adoum, Anne Tounsia
AU - Leitch, Victoria D.
AU - Logan, John G.
AU - Waung, Julian A.
AU - Ghirardello, Elena
AU - Southam, Lorraine
AU - Youlten, Scott E.
AU - Wilkinson, J. Mark
AU - McAninch, Elizabeth A.
AU - Vancollie, Valerie E.
AU - Kussy, Fiona
AU - White, Jacqueline K.
AU - Lelliott, Christopher J.
AU - Adams, David J.
AU - Jacques, Richard
AU - Bianco, Antonio C.
AU - Boyde, Alan
AU - Zeggini, Eleftheria
AU - Croucher, Peter I.
AU - Williams, Graham R.
AU - Bassett, J. H.Duncan
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-20761-5
DO - 10.1038/s41467-020-20761-5
M3 - Article
C2 - 33473114
AN - SCOPUS:85099680503
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 467
ER -