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LncPVT1 promotes cartilage degradation in diabetic OA mice by downregulating miR-146a and activating TGF-β/SMAD4 signaling

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Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

To investigate the role of LncRNA PVT1 (plasmacytoma variant translocation 1) in hyperglycemia-triggered cartilage damage using the diabetic osteoarthritis (OA) mice model.

Materials and methods

Streptozotocin (STZ) was used to induce mouse diabetes. Knee OA model was induced through transection of anterior cruciate ligament (ACLT). Severity of arthritis was assessed histologically by Safranin O-Fast Green Staining using Mankin Scores. LncRNA PVT1 and miR-146a were detected by real-time polymerase chain reaction (PCR) in cartilage tissue. Moreover, the interaction among PVT1, miR-146a, and SMAD4 was examined by luciferase reporter assays. Mice were injected intra-articularly with ad-siRNA-PVT1 and ad-siRNA scramble control. Articular concentrations of TNF-α, IL-1, IL-6 and TGF-β1 were determined using enzyme-linked immunosorbent assay. Levels of type II Collagen (COL2A1), TGF-β1, p-SMAD2, SMAD2, p-SMAD3, SMAD3, SMAD4 and nuclear SMAD4 were detected by western blot analysis.

Results

PVT1 expression was significantly increased, whereas miR-146a was markedly decreased in diabetic OA mice than in non-diabetic OA and control. Increased PVT1 expression in diabetic OA mice was significantly associated with Mankin score and reduced miR-146a as well as Collagen alpha-1(II) (COL2A1) expressions. In vivo, intra-articular injection of ad-siRNA-PVT1 efficiently increased miR-146a and COL2A1 expressions, alleviated joint inflammation, decreased the expression of pro-inflammatory mediators, and suppressed TGF-β/SMAD4 pathway in diabetic OA mice.

Conclusions

Our results demonstrate LncRNA PVT1 is involved in cartilage degradation in diabetic OA and correlated with disease severity. Efficiency of ad-siRNA-PVT1 in controlling joint inflammation in diabetic OA mice is associated with the suppression of the expression of miR-146a, pro-inflammatory cytokines and activation of TGF-β/SMAD4 pathway.

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Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. This work was supported by the Natural Science Foundation of Guangdong Province (Grant Number 2016A030313100), the National Natural Science Foundation of China (Grant Number 81601219), and the China Postdoctoral Science Foundation (Grant Numbers 2015M582480 and 2017T100660), Medical Scientific Research Foundation of Guangdong Province (A2019100).

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Third Hospital of Shijiazhuang, ChangAn District, , Shijiazhuang, 050011, HeBei, China

    Yan-Zhi Wang,  Yao-Li, Sheng-Kai Liang, Luo-Bin Ding,  Feng-Li & Jian Guan

  2. Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital of Jinan University, Road West No. 613, Huang-Pu, Guangzhou, 510632, GuangDong, China

    Hua-Jun Wang

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  1. Yan-Zhi Wang
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Correspondence to Jian Guan or Hua-Jun Wang.

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Wang, YZ., Yao-Li, Liang, SK. et al. LncPVT1 promotes cartilage degradation in diabetic OA mice by downregulating miR-146a and activating TGF-β/SMAD4 signaling. J Bone Miner Metab 39, 534–546 (2021). https://doi.org/10.1007/s00774-020-01199-7

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  • DOI: https://doi.org/10.1007/s00774-020-01199-7

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