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Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis
  1. Lan Zhao1,
  2. Jian Huang1,
  3. Yunshan Fan1,2,
  4. Jun Li1,
  5. Tianming You1,
  6. Shisheng He2,
  7. Guozhi Xiao1,
  8. Di Chen1
  1. 1 Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois, USA
  2. 2 Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
  1. Correspondence to Professor Di Chen, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, United States; di_chen{at}rush.edu; Dr Jian Huang, Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, United States; jian_huang{at}rush.edu

Abstract

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-1β (IL-1β) 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-1β and NGF, in a surgically induced OA mouse model. We also tested triple ablations of NGF, MMP13 and IL-1β.

Results Loss-of-function of NGF palliates pain but worsens joint damage in the surgically induced OA model. Ablation of MMP13 or IL-1β reduces the expression of cartilage-degrading enzymes and attenuates structural deterioration. Targeting both MMP13 and IL-1β significantly mitigates the adverse effects of NGF blockade on the joints.

Conclusions CRISPR-mediated ablation of NGF alleviates OA pain, and deletion of MMP13-1β or IL-1β attenuates structural damage in a post-traumatic OA model. Multiplex ablations of NGF, MMP13 and IL-1β 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.

  • osteoarthritis
  • knee osteoarthritis
  • treatment
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Footnotes

  • JH and DC are joint senior authors.

  • LZ, JH and YF contributed equally.

  • Handling editor Josef S Smolen

  • Contributors JH designed the study and wrote the manuscript. LZ, JH and DC designed the experiments. LZ, JH, YF, JL and TY performed research. SH and GX provided expertise and feedback. JH and DC supervised the study. LZ and DC revised the manuscript.

  • Funding Grants R01AR054465 and R01AR070222 of National Institutes of Health; the Rush 2015 Schweppe/Armour bequest Pilot Project; the National Natural Science Foundation of China (81630066).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Institutional Review Board of Rush University Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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