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CUL4B promotes the pathology of adjuvant-induced arthritis in rats through the canonical Wnt signaling

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Abstract

This work aims to discuss the possibility that disordered CUL4B was involved in the pathogenesis of adjuvant-induced arthritis (AIA) in rats. Synovium and FLS from AIA rats both showed increased CUL4B and β-catenin, and up-regulated CUL4B enhanced the canonical Wnt signaling by targeting the GSK3β. Increased CUL4B promoted the FLS abnormal proliferation, activated the secretion of IL-1β and IL-8, and promoted the production of AIA pathology gene MMP3 and fibronectin. Furthermore, miR-101-3p was significantly down-regulated in AIA rats compared with controls, and transfection of AIA FLS with miR-101-3p mimics significantly down-regulated the CUL4B expression, whereas transfection with miR-101-3p inhibitors resulted in an opposite observation. The dual-luciferase reporter assay confirmed that the CUL4B was a direct target of miR-101-3p, and further analysis suggested that lowly expressed miR-101-3p contributed to disordered CUL4B activating the canonical Wnt signaling pathway and further promoting the development of AIA rats. Thus clarification of the CUL4B roles in the pathogenesis of AIA rats and corresponding mechanisms will contribute to the disease diagnosis and treatment for rheumatoid arthritis (RA) patients.

Key messages

  • CUL4B expression is up-regulated in synovium and FLS from AIA rats.

  • Increased CUL4B promotes the canonical Wnt signaling.

  • Increased CUL4B promotes the pathogenesis of AIA rats.

  • Decreased miR-101-3p contributes to disordered CUL4B.

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Abbreviations

RA:

rheumatoid arthritis

CUL4B:

Cullin 4B

AIA:

adjuvant-induced arthritis

RING:

really interesting new gene

CRLs:

Cullin-RING ubiquitin ligase

PRC2:

polycomb repressive complex 2

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide

DMSO:

dimethyl sulfoxide

FBS:

fetal bovine serum

WDR5:

WD repeat containing protein5

PrxIII:

peroxiredoxin III

SDF-1:

stromal cell derived factor 1

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Authors and Affiliations

  1. Department of Pharmacy, School of Life and Health Science, Anhui Science and Technology University, Donghua Road, Fengyang, 233100, Anhui Province, China

    Chenggui Miao, Hao Yu, Lili Zhou, Guoliang Zhou & Chuanlei Zhao

  2. Department of Orthopaedics, 4th Affiliated Hospital, Anhui Medical University, Hefei, 230032, China

    Jun Chang

  3. State Key Laboratory of Tea Biology and Resource Utilization, College of Tea and Food Science and Technology, Anhui Agricultural University, Hefei, 230036, China

    Guoxue Zhang

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  1. Chenggui Miao
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  2. Jun Chang
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  3. Guoxue Zhang
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  4. Hao Yu
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  5. Lili Zhou
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  6. Guoliang Zhou
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  7. Chuanlei Zhao
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Correspondence to Chenggui Miao.

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Miao, C., Chang, J., Zhang, G. et al. CUL4B promotes the pathology of adjuvant-induced arthritis in rats through the canonical Wnt signaling. J Mol Med 96, 495–511 (2018). https://doi.org/10.1007/s00109-018-1635-8

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  • DOI: https://doi.org/10.1007/s00109-018-1635-8

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