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LncRNA KCNQ1OT1 attenuates osteoarthritic chondrocyte dysfunction via the miR-218-5p/PIK3C2A axis

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Abstract

The occurrence of osteoarthritis is closely related to chondrocyte dysfunction caused by cellular inflammatory response and matrix degradation, which seriously affect the quality of life of patients. Therefore, this study aimed to investigate the role of potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (KCNQ1OT1), a member of the lncRNA voltage-gated channel subfamily Q, in the development of osteoarthritis. In this study, RT-qPCR results showed that KCNQ1OT1 expression was downregulated in osteoarthritic chondrocytes compared with normal chondrocytes. In addition, upregulation of KCNQ1OT1 significantly enhanced the viability of osteoarthritic chondrocytes, inhibited cell apoptosis, and reduced the release of inflammatory cytokines and metal matrix enzymes. Next, bioinformatics analysis and luciferase reporter gene analysis predicted and validated the targeting relationship between KCNQ1OT1 and miR-218-5p. We found that the expression of miR-218-5p was significantly upregulated in osteoarthritic chondrocytes, and knockdown of miR-218-5p significantly enhanced the viability of osteoarthritic chondrocytes, inhibited apoptosis, and decreased the abundance of inflammatory cytokines and metal matrix enzymes. Furthermore, the targeting relationship between miR-218-5p and recombinant phosphoinositide-3-kinase class-2-alpha polypeptide (PIK3C2A) was identified, and overexpression of PIK3C2A enhanced cell viability, and reduced apoptosis and secretion of inflammatory factors. Finally, we found that miR-218-5p overexpression reversed the protective effect of overexpression of KCNQ1OT1 or PIK3C2A on osteoarthritic chondrocytes. In conclusion, our results demonstrated that KCNQ1OT1 upregulated PIK3C2A and activated the PI3K/AKT/mTOR pathway to reduce chondrocyte dysfunction by targeting miR-218-5p, providing new insights into the pathogenesis of osteoarthritis.

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Abbreviations

LncRNA:

Long non-coding RNA

siRNA:

Small interference RNA

ceRNA:

Competing endogenous RNA

KCNQ1OT1:

Potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1

PIK3C2A:

Recombinant phosphoinositide-3-kinase class-2-alpha polypeptide

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

TNF-α:

Tumor necrosis factor-α

COX-2:

Cyclooxygenase-2

MMP-13:

Matrix metallopeptidase-13

ADAMTS-5:

ADAM metallopeptidase with thrombospondin type 1 motif 5

COL2A1:

Collagen type II alpha 1 chain

ECM:

Extracellular matrix components

OARSI:

Osteoarthritis Research Society International

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

PVDF:

Polyvinylidene difluoride

HRP:

Horseradish peroxidase

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Authors and Affiliations

  1. Department of Orthopaedics, The First Hospital of Jilin University, 3302 Jilin Road, Changchun, 130000, Jilin, China

    Yijun Liu, Ding Zhao & Fupeng Ding

  2. Department of Anesthesiology, The First Hospital of Jilin University, Changchun, 130000, Jilin, China

    Xue Wang

  3. The Third Department of Radiotherapy, Jilin Provincial Tumor Hospital, Changchun, 130012, Jilin, China

    Ying Dong

Authors
  1. Yijun Liu
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  2. Ding Zhao
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  3. Xue Wang
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  4. Ying Dong
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  5. Fupeng Ding
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Corresponding author

Correspondence to Fupeng Ding.

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Ethical approval

The present study and the associated experimental protocols (human experiments) were performed in compliance with ethical guidelines and approved by the Institute Research Medical Ethics Committee of the First Hospital of Jilin University, Changchun, Jilin, China. (approval no. FH2016-184). All osteoarthritis tissues and non-osteoarthritis tissues were also used in accordance with the Helsinki declaration.

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Fully informed consent was obtained from every participant prior to enrollment.

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The authors declare that they have no conflict of interest.

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Liu, Y., Zhao, D., Wang, X. et al. LncRNA KCNQ1OT1 attenuates osteoarthritic chondrocyte dysfunction via the miR-218-5p/PIK3C2A axis. Cell Tissue Res 385, 115–126 (2021). https://doi.org/10.1007/s00441-021-03441-8

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  • DOI: https://doi.org/10.1007/s00441-021-03441-8

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