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Precise targeting of miR-141/200c cluster in chondrocytes attenuates osteoarthritis development
  1. Ming-Liang Ji1,
  2. Hua Jiang2,
  3. Fei Wu1,
  4. Rui Geng1,
  5. Li kun Ya1,
  6. Yu Cheng Lin1,
  7. Ji Hao Xu1,
  8. Xiao Tao Wu1,
  9. Jun Lu3
  1. 1 The department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
  2. 2 Department of Spine Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
  3. 3 Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
  1. Correspondence to Dr Jun Lu, Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China; junlusuper{at}163.com

Abstract

Objectives Despite preclinical studies involving miRNA therapeutics conducted in osteoarthritis (OA) over the years, none of these miRNAs have yet translated to clinical applications, owing largely to the lack of efficient intra-articular (IA) delivery systems. Here, we investigated therapeutic efficacy of the chondrocyte-specific aptamer-decorated PEGylated polyamidoamine nanoparticles (NPs)-based miRNAs delivery for OA.

Methods The role of miR-141/200c cluster during skeletal and OA development was examined by miR-141/200cflox/flox mice and Col2a1-CreERT2; miR-141/200cflox/flox mice. Histological analysis was performed in mouse joints and human cartilage specimens. Chondrocyte-specific aptamer-decorated NPs was designed, and its penetration, stability and safety were evaluated. OA progression was assessed by micro-CT analysis, X-ray and Osteoarthritis Research Society International scores after destabilising the medial meniscus surgery with miR-141/200c manipulation by NPs IA injection. Mass spectrometry analysis, molecular docking and molecular dynamics simulations were performed to investigate the interaction between aptamer and receptor.

Results Increased retention of NPs inside joint space is observed. The NPs are freely and deeply penetrant to mice and human cartilage, and unexpectedly persist in chondrocytes for at least 5 weeks. OA chondrocytes microenviroment improves endo/lysosomal escape of microRNAs (miRNAs). Therapeutically, IA injection of miR-141/200c inhibitors provides strong chondroprotection, whereas ectopic expression of miR-141/200c exacerbates OA. Mechanistically, miR-141/200c promotes OA by targeting SIRT1, which acetylates histone in the promoters of interleukin 6 (IL-6), thereby activating IL-6/STAT3 pathway.

Conclusions Our findings indicate that this nanocarrier can optimise the transport kinetics of miR-141/200c into chondrocytes, fostering miRNA-specific disease-modifying OA drugs development.

  • osteoarthritis
  • knee
  • chondrocytes
  • pharmacokinetics
  • therapeutics

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors All authors were involved in drafting or critically revising the manuscript for important intellectual content, and all authors approved the final version for publication. JL, XTW, M-LJ and HJ conceived the ideas and designed the experiments. M-LJ, FW, RG, LKY, YCL and JHX conducted experiments and analySed the data. JL and M-LJ interpreted the data and wrote the manuscript.

  • Funding This work is supported by The National Science Foundation of of China (No. 81972105, No. 81672159 and No. 81860406), and the Fundamental Research Funds for the Central Universities (No. 2242019K3DZ05).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Protocol approved by the ethical committee of Zhongda Hospital, Southeast University.

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

  • Data availability statement Data are available on reasonable request.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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