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Potential therapeutic strategies for osteoarthritis via CRISPR/Cas9 mediated gene editing

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A Correction to this article was published on 22 December 2023

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Abstract

Osteoarthritis (OA) is an incapacitating and one of the most common physically degenerative conditions with an assorted etiology and a highly complicated molecular mechanism that to date lacks an efficient treatment. The capacity to design biological networks and accurately modify existing genomic sites holds an apt potential for applications across medical and biotechnological sciences. One of these highly specific genomes editing technologies is the CRISPR/Cas9 mechanism, referred to as the clustered regularly interspaced short palindromic repeats, which is a defense mechanism constituted by CRISPR associated protein 9 (Cas9) directed by small non-coding RNAs (sncRNA) that bind to target DNA through Watson-Crick base pairing rules where subsequent repair of the target DNA is initiated. Up-to-date research has established the effectiveness of the CRISPR/Cas9 mechanism in targeting the genetic and epigenetic alterations in OA by suppressing or deleting gene expressions and eventually distributing distinctive anti-arthritic properties in both in vitro and in vivo osteoarthritic models. This review aims to epitomize the role of this high-throughput and multiplexed gene editing method as an analogous therapeutic strategy that could greatly facilitate the clinical development of OA-related treatments since it’s reportedly an easy, minimally invasive technique, and a comparatively less painful method for osteoarthritic patients.

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Abbreviations

CRISPR/Cas9:

Clustered Regularly Interspaced Short palindromic repeats and CRISPR-associated protein 9

OA:

Osteoarthritis

RA:

Rheumatoid Arthritis

MSCs:

Mesenchymal Stem Cells

DNA:

Deoxyribonucleic Acid

gRNA:

Guide Ribonucleic Acid

SBP:

Subchondral Bone Plate

SBT:

Subchondral Bone Trabeculae

SBMLs:

Subchondral Bone Marrow Lesions

SASP:

Senescence-Associated Secretory Phenotype

MMPs:

Matrix metalloproteinases

ECM:

Extracellular Matrix

ACAN:

Aggrecan

TNF:

Tumor Necrosis Factor

TNFα:

Tumor Necrosis Factor alpha

ADAMTS:

A Disintegrin and Metalloproteinase with Thrombospondin motifs

IL:

Interleukin

Th2:

T helper cell type 2

CD4+:

Cluster of differentiation 4

sIL-4R:

Soluble interleukin-4 receptor

sIL-6R:

Soluble interleukin-6 receptor

mIL-6R:

Membrane-bound IL-6 receptor

FLS:

Fibroblast-like Synoviocytes

ADAM17/TACE:

A Disintegrin and Metalloprotease 17/Tumor Necrosis Factor-Alpha Converting Enzyme

CD130/gp130:

Glycoprotein 130

sgp130:

Soluble glycoprotein 130

mgp130:

Membrane glycoprotein 130

SMAD:

Small Mothers Against Decapentaplegic

ERK1/2MAP:

Extracellular Signal-regulated Kinase 1/2 Mitogen-activated Protein

BMP:

Bone Morphogenetic Proteins

TGF-β:

Transforming Growth Factor Beta

NKX3-2:

NK3 homeobox 2

PDGF:

Platelet-derived Growth Factor

VSMCs:

Vascular Smooth Muscle Cells

FGF:

Fibroblast Growth Factors

CDMP-1:

Cartilage-Derived Morphogenetic Protein

ROS:

Reactive Oxygen Species

OH −:

Hydroxyl Radical

H2O2 −:

Hydrogen Peroxide

O2 −:

Superoxide Anion

NO −:

Nitric Oxide

OCl −:

Hypochlorite Ion

NADPH:

Nicotinamide Adenine Dinucleotide Phosphate

LPO:

Lipid-based Peroxidation

LOOH:

Lipid Hydroperoxides

ox-LDL:

Oxidized Low-Density Lipoprotein

NOS:

Nitrous Oxide Synthase

PI3K/Akt:

Phosphatidylinositol 3-Kinase / Protein Kinase B

MEK/ERK:

Mitogen-activated Protein Kinase / Extracellular Signal-regulated Kinase

iNOS:

Inducible Nitric Oxide Synthase

NF-κB:

Nuclear Factor kappa-light-chain-enhancer of activated B cells

PGE2:

Prostaglandin E2

ICE:

Interleukin-1beta Converting Enzyme

NSAIDs:

Non-Steroidal Anti-Inflammatory Drugs

HA:

Hyaluronic Acid / Hyaluronate

PRP:

Platelet-Rich Plasma

BMAC:

Bone Marrow Aspirate Concentrate

AD-MSCs:

Adipose-Derived Mesenchymal Stem Cells

VEGF:

Vascular Endothelial Growth Factor

VAS:

Visual Analogue Scale

WOMAC:

The Western Ontario and McMaster Universities Arthritis Index

SpCas-9:

Streptococcus pyogenes Cas9 nuclease

PAM:

Protospacer Adjacent Motif

RuvC:

Recombination UV C resolvase

HNH:

Homing endonuclease

REC:

Recognition lobe

NUC:

Nuclease lobe

crRNA:

Crispr RNA

sncRNA:

Small non-coding RNA

tracrRNA:

Trans-activating Crispr RNA

DSBs:

Double-Stranded Breaks

HDR:

Homology-Directed Repair

NHEJ:

Non-homologous End Joining

AAV:

Adeno-associated virus

rAAV:

Recombinant Adeno-associated virus

scAAV:

Self-complementary recombinant Adeno-associated virus

cDNA:

Complementary DNA

+ ssRNA:

Positive-sense single RNA

TILs:

Tumor Infiltrating Lymphocytes

HSP70:

Heat Shock Protein 70

CHS:

Chondroitin Sulfate

ELMO1:

Engulfment and Cell Motility 1

SOX9:

SRY-Box Transcription Factor 9

USP11:

Ubiquitin Specific Peptidase 11

WNT 16:

Int/Wingless Protein

BGLAP:

Bone Gamma-Carboxyglutamate Protein

miR-140:

Micro RNA 140

NcRNA:

Non-coding RNA

HAS2:

Hyaluronan Synthase 2

STNFR1α:

Soluble Tumor Necrosis Factor Receptor 1

IL-1RA:

Interleukin 1 Beta Receptor Antagonist

PRG4:

Proteoglycan 4

DANCR:

Differentiation Antagonizing Non-Protein Coding RNA

TRPV4:

Transient Receptor Potential Cation Channel Subfamily V Member 4

CX43:

Connexin 43

COL2A1:

Collagen, Type II, Alpha 1

NGF:

Nerve Growth Factor

CBX4:

Chromobox 4

FOXD1:

Forkhead Box D1

YAP:

Yes-associated Protein 1

iPSCs:

Induced Pluripotent Stem Cells

RCS:

Rat Chondrosarcoma Cell Line

ASC:

Adipose Stromal Cells

FDA:

The Food and Drug Administration

CRISPRi:

CRISPR interference

HDAd:

Helper-Dependent Adenoviral Vectors

DGCR8:

DiGeorge critical region-8

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Funding

This work was supported by grants by Zhejiang Provincial Natural Science Foundation of China (LZ23H140001), Zhejiang Qianjiang Talent Program (21040040-E), a startup grant from Zhejiang Sci-Tech University (18042290-Y), the Fundamental Research Funds of Zhejiang Sci-Tech University (2021Q031), funds from National Natural Science Foundation of China (81900806, 81400489), Jiaxing Science Technology Foundation (2023AY11045, 2020AY10001), Zhejiang Health Foundation (2022507032), Social Development Public Welfare Foundation of Ningbo (No.202002N3150, 2022S035), Innovation Project of Distinguished Medical Team in Ningbo (No.2022020405). We apologize to the many researchers whose work could not be cited due to space limitations.

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Authors and Affiliations

  1. College of Life Science and Medicine, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China

    Rexhina Vlashi & Guiqian Chen

  2. Department of Orthopedics, Jiaxing Key Laboratory for Minimally Invasive Surgery in Orthopaedics & Skeletal Regenerative Medicine, Zhejiang Rongjun Hospital, Jiaxing, 314001, China

    Xingen Zhang

  3. The Central Laboratory of Birth Defects Prevention and Control, Ningbo Women and Children’s Hospital, Ningbo, China

    Haibo Li

  4. Ningbo Key Laboratory for the Prevention and Treatment of Embryogenic Diseases, Ningbo Women and Children’s Hospital, Ningbo, China

    Haibo Li

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  1. Rexhina Vlashi
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  2. Xingen Zhang
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  3. Haibo Li
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  4. Guiqian Chen
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RV: data analysis, literature formation. XZ, HL: literature formation, supervision, GC: literature formation, supervision, and grant holder.

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Correspondence to Haibo Li or Guiqian Chen.

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Vlashi, R., Zhang, X., Li, H. et al. Potential therapeutic strategies for osteoarthritis via CRISPR/Cas9 mediated gene editing. Rev Endocr Metab Disord 25, 339–367 (2024). https://doi.org/10.1007/s11154-023-09860-y

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