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Cellular and Molecular Life Sciences

, Volume 74, Issue 19, pp 3451–3465 | Cite as

Emerging potential of gene silencing approaches targeting anti-chondrogenic factors for cell-based cartilage repair

  • Andrea Lolli
  • Letizia Penolazzi
  • Roberto Narcisi
  • Gerjo J. V. M. van Osch
  • Roberta Piva
Review

Abstract

The field of cartilage repair has exponentially been growing over the past decade. Here, we discuss the possibility to achieve satisfactory regeneration of articular cartilage by means of human mesenchymal stem cells (hMSCs) depleted of anti-chondrogenic factors and implanted in the site of injury. Different types of molecules including transcription factors, transcriptional co-regulators, secreted proteins, and microRNAs have recently been identified as negative modulators of chondroprogenitor differentiation and chondrocyte function. We review the current knowledge about these molecules as potential targets for gene knockdown strategies using RNA interference (RNAi) tools that allow the specific suppression of gene function. The critical issues regarding the optimization of the gene silencing approach as well as the delivery strategies are discussed. We anticipate that further development of these techniques will lead to the generation of implantable hMSCs with enhanced potential to regenerate articular cartilage damaged by injury, disease, or aging.

Keywords

Gene silencing RNA interference MicroRNA Cartilage repair Chondrogenesis Mesenchymal stem cells Anti-chondrogenic regulators 

Abbreviations

AIMP1

Aminoacyl tRNA synthetase complex interacting multifunctional protein 1

ANGPTL4

Angiopoietin-like 4

BMP

Bone morphogenetic protein

circRNA

Circular RNA

ECM

Extracellular matrix

EMT

Epithelial-to-mesenchymal transition

ERK

Extracellular signal-regulated kinase

EV

Extracellular vesicle

FGF

Fibroblasts growth factor

GAG

Glycosaminoglycan

hMSCs

Human mesenchymal stem cells

IGF

Insulin-like growth factor

IHH

Indian hedgehog

IKK

IkB kinase

JNK

C-Jun N-terminal kinase

KDM2A

Lysine demethylase 2A

lncRNA

Long non-coding RNA

MAPK

Mitogen-activated protein kinase

MCC

Mandibular condylar cartilage

MEK

Mitogen-activated protein kinase

MMP

Matrix metalloproteinase

NP

Nanoparticle

OA

Osteoarthritis

p53R2

p53-Inducible ribonucleotide reductase

PAMAM

Polyamidoamine

PEI

Polyethylenimine

PHD2

Prolyl hydroxylase domain-containing protein 2

PLGA

Poly(d,l-lactide-co-glycolide)

PLL

Poly-l-lysine

PNA

Peptide nucleic acid

QD

Quantum dot

RISC

RNA-induced silencing complex

RNAi

RNA interference

RUNX2

Runt-related transcription factor 2

shRNA

Short hairpin RNA

siRNA

Short interfering RNA

SOX

SRY (sex determining region Y)-box

TF

Transcription factor

TGF

Transforming growth factor

TGIF1

TGF-β induced factor homeobox 1

VEGF

Vascular endothelial growth factor

Notes

Acknowledgements

A.L. is funded by the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska Curie Grant agreement No 642414. R.N. is supported by the VENI Grant by STW (13659). The authors are grateful to Dr. E. J. Farrell, Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center, for English revision of the manuscript.

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Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Department of Orthopaedics, Erasmus MCUniversity Medical CenterRotterdamThe Netherlands
  2. 2.Department of Biomedical and Specialty Surgical SciencesUniversity of FerraraFerraraItaly
  3. 3.Department of Otorhinolaryngology, Erasmus MCUniversity Medical CenterRotterdamThe Netherlands

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