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Osteoarthritis Cartilage. 2018 Jul;26(7):966-977. doi: 10.1016/j.joca.2018.04.002. Epub 2018 Apr 12.

Wnt5a suppresses inflammation-driven intervertebral disc degeneration via a TNF-α/NF-κB-Wnt5a negative-feedback loop.

Author information

1
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: sdlizemin@163.com.
2
Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China. Electronic address: 05213381@163.com.
3
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: 858330676@qq.com.
4
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: panhehai@foxmail.com.
5
Department of Orthopedic Surgery, Guangzhou Chest Hospital, Guangzhou, 510080, China. Electronic address: lisbylee@qq.com.
6
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: 476268201@qq.com.
7
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: zhangjianspine@163.com.
8
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: zhengzm1@163.com.
9
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: zzuwjr@163.com.
10
Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: liuhui58@mail.sysu.edu.cn.

Abstract

OBJECTIVE:

This study was to investigate the molecular role of Wnt5a on inflammation-driven intervertebral disc degeneration (IVDD).

METHODS:

The expression of Wnt5a was analyzed in human nucleus pulposus (NP) tissues with immunohistochemical staining. The effects of Wnt5a on matrix production were assessed by RT-qPCR and western blotting. Small interfering RNAs (siRNAs), promoter deletion assay, and promoter binding site mutant were used to reveal the molecular role of Wnt5a in TNF-α-induced matrix metalloproteinase (MMP) expression. The regulatory effects of TNF-α on Wnt5a were investigated with pharmachemical inhibitors and siRNA experiment.

RESULTS:

The expression of Wnt5a was elevated in moderately degenerated human NP tissue with similar expression pattern of TNF-α. In NP cells, Wnt5a significantly increased aggrecan and collagen II expression. Inhibition of JNK or interfering Sox9 gene expression significantly suppressed Wnt5a-induced matrix production. AP-1(JunB) binding sites were located in Sox9 promoter and mutation of these sites sabotaged Wnt5a-induced Sox9 up-regulation and subsequent matrix genes expression. Notably, Wnt5a, which was induced by TNF-α, on the other way round suppressed TNF-α-NF-κB (p65) signaling and subsequent MMPs expression. In vivo studies with MR imaging confirmed the protective role of Wnt5a in IVDD.

CONCLUSIONS:

Wnt5a, which can be induced by TNF-α, increased matrix production in a Sox9-dependent manner through the activation of JNK-AP1 (JunB) signaling, and antagonized TNF-α-induced up-regulation of MMPs through the inhibition of NF-κB signaling. It indicates that Wnt5a suppresses IVDD through a TNF-α/NF-κB-Wnt5a negative-feedback loop.

KEYWORDS:

Intervertebral disc degeneration; Negative feedback loop; Nucleus pulposus; TNF-α; Wnt5a

PMID:
29656141
DOI:
10.1016/j.joca.2018.04.002
[Indexed for MEDLINE]
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