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Blockade of adiponectin receptor 1 signaling inhibits synovial inflammation and alleviates joint damage in collagen-induced arthritis

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Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objectives

Adiponectin (AD) highly expressed in synovial tissue correlates closely with progressive bone erosion in rheumatoid arthritis (RA). However, it remains unknown whether AD receptor mediates the pathogenesis of RA. This study aimed to investigate the effects of adiponectin receptor 1 (AdipoR1) signaling on synovial inflammation and joint damage in collagen-induced arthritis.

Methods

AD and AdipoR1 expression in synovial tissue of RA and osteoarthritis (OA) patients were tested by PCR and western blotting. The frequency of AdipoR1 on RA synovial fibroblasts (RASFs) was examined by flow cytometry after stimulation with AD, IL-6, or TNF-α. AdipoR1 was knocked down in human RASF cell line (MH7A) and CIA mice joints using lentiviral particles carrying the AdipoR1 short hairpin RNA (shAdipoR1). Both the proliferation and apoptosis of MH7A and the secretion of inflammatory factors from MH7A were examined in vitro. The therapeutic effect of local AdipoR1 inhibition on CIA mice was assessed in vivo.

Results

Both the expression of AD and AdipoR1 were significantly higher in RA synovial tissue. AdipoR1 on RASFs was upregulated by AD. Silencing AdipoR1 remarkably reduced lipopolysaccharides-induced proliferation and promoted the apoptosis of MH7A. Moreover, AdipoR1 knockdown inhibited the release of inflammatory factors in vitro. In CIA mice, local AdipoR1 inhibition effectively decreased joint inflammation and alleviated bone destruction via suppressing RANKL and RANKL/OPG ratio in vivo.

Conclusions

AdipoR1 signaling participates in the process of synovial inflammation and joint damage in CIA. Local blockade of AdipoR1 might be a new target for the clinical treatment of RA.

Key points

• Local AdipoR1 inhibition decreased joint inflammation and alleviated bone destruction in CIA.

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Data availability

Data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

Abbreviations

AD :

Adiponectin

RA :

Rheumatoid arthritis

AdipoR :

Adiponectin receptor

MH7A :

A human rheumatoid arthritis synovial fibroblast cell line

CIA :

Collagen-induced arthritis

ShRNAs :

Short hairpin RNAs

LPS :

Lipopolysaccharides

RANKL :

Receptor activator of nuclear factor к B ligand

OPG :

Osteoprotegerin

TNF-α :

Tumor necrosis factor

IL :

Interleukin

RASFs :

Rheumatoid arthritis synovial fibroblasts

OA :

Osteoarthritis

HC:

Healthy controls

Lenti-shAdipoR1 :

Lentiviral particles carrying the AdipoR1 short hairpin RNA

shNC :

Negative control shRNA

CCK-8 :

Cell counting kit 8

PI :

Propidium iodide

CII :

Bovine collagen type II

H&E :

Hematoxylin and eosin

Micro-CT :

Micro-computed tomography

ANOVA :

One-way analysis of variance

GFP :

Green fluorescent protein

O.D. :

Optical density

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Funding

This study was funded by the National Natural Science Foundation of China (NSFC) (81671615, 81771758, and 81501393) and the Special Project of Clinical Medicine from Jiangsu Province (BL2013034).

Author information

Author notes

  1. Yani Wang and Rui Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China

    Yani Wang, Rui Liu, Pengfei Zhao, Qian Zhang, Yingheng Huang, Lei Wang, Chengyin Lv, Nan Che, Wenfeng Tan & Miaojia Zhang

Authors
  1. Yani Wang
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  2. Rui Liu
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  3. Pengfei Zhao
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  4. Qian Zhang
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Contributions

Miaojia Zhang and Wenfeng Tan conceived and designed the experiments. Yani Wang, Rui Liu, Pengfei Zhao, Qian Zhang, Yingheng Huang, and Lei Wang performed experiments. Chengyin Lv and Nan Che collected samples. Yani Wang and Rui Liu wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Miaojia Zhang.

Ethics declarations

Ethics approval

The protocol was approved by the Ethics Committee at the First Affiliated Hospital of Nanjing Medical University (2013-SR-178).

Consent to participate

The purpose of the study was explained to the participants, and the present study was performed after obtaining written informed consent.

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Prior to data collection, the purpose of the study was explained to the participants and their informed consent was recorded.

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None

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Supplementary Information

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Supplementary Fig. S1

The expression of AdipoR1 was verified after lentivirus transfaction in MH7A.

(A) The expression of AdipoR1 after shRNA/GFP lentivirus transfaction in MH7A. (B) The AdipoR1 mRNA expression after shRNA lentivirus transfaction in MH7A was verified by PCR (n=3). (C) The AdipoR1 protein expression after shRNA lentivirus transfaction in MH7A was verified by western blotting. Values are presented as the means ± S.D. **P<0.01. (TIF 5.44 mb)

High resolution image (PNG 423 kb)

Supplementary Fig. S2

The expression of AdipoR1 was verified after lentivirus injection into CIA mice intraarticularly.

(A) The AdipoR1 mRNA expression was verified by PCR after shRNA lentivirus injection (n=3). (B) The AdipoR1 protein expression was verified by western blotting after shRNA lentivirus injection. Values are presented as the means ± S.D. *P<0.05. (TIF 4.59 mb)

High resolution image (PNG 202 kb)

Supplementary file3 (DOC 10390 KB)

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Wang, Y., Liu, R., Zhao, P. et al. Blockade of adiponectin receptor 1 signaling inhibits synovial inflammation and alleviates joint damage in collagen-induced arthritis. Clin Rheumatol 41, 255–264 (2022). https://doi.org/10.1007/s10067-021-05846-w

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  • DOI: https://doi.org/10.1007/s10067-021-05846-w

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