Journal
ANNALS OF THE RHEUMATIC DISEASES
Volume 78, Issue 5, Pages 676-682Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2018-214724
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Funding
- National Institutes of Health [R01AR054465, R01AR070222]
- [81630066]
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Objectives Osteoarthritis (OA) is a painful and debilitating disease and it is associated with aberrant upregulation of multiple factors, including matrix metalloproteinase 13 (MMP13), interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF). In this study, we aimed to use the CRISPR/Cas9 technology, a highly efficient gene-editing tool, to study whether the ablation of OA-associated genes has OA-modifying effects. Methods We performed intra-articular injection of adeno-associated virus, which expressed CRISPR/Cas9 components to target each of the genes encoding MMP13, IL-1 beta and NGF, in a surgically induced OA mouse model. We also tested triple ablations of NGF, MMP13 and IL-1 beta. Results Loss-of-function of NGF palliates pain but worsens joint damage in the surgically induced OA model. Ablation of MMP13 or IL-1 beta reduces the expression of cartilage-degrading enzymes and attenuates structural deterioration. Targeting both MMP13 and IL-1 beta significantly mitigates the adverse effects of NGF blockade on the joints. Conclusions CRISPR-mediated ablation of NGF alleviates OA pain, and deletion of MMP13-1 beta or IL-1 beta attenuates structural damage in a post-traumatic OA model. Multiplex ablations of NGF, MMP13 and IL-1 beta provide benefits on both pain management and joint structure maintenance. Our results suggest that CRISPR-based gene editing is useful for the identification of promising drug targets and the development of feasible therapeutic strategies for OA treatment.
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