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Dickkopf-1 perpetuated synovial fibroblast activation and synovial angiogenesis in rheumatoid arthritis

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Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objective

Dickkopf-1 (Dkk-1), a regulatory molecule of the Wnt pathway, is elevated and leads to bone resorption in patients with RA. This study is aimed to investigate the contribution of Dkk-1 to synovial inflammation and synovial fibroblast-mediated angiogenesis in RA.

Methods

The expression of Dkk-1 in RA synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF) was detected by real-time PCR and ELISA, respectively. RASF were stimulated with different pro-inflammatory factors. The expression of angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF was analyzed by real-time PCR when Dkk-1 was inhibited or overexpressed. Meanwhile, the concentrations of MCP-1, IL-6, IL-8, and MMP-3 in the cell culture supernatant were assessed by ELISA. The effects of Dkk-1 on the MAPK signaling pathway were evaluated by western blot. Matrigel tube formation assay was employed to reveal the direct and indirect effects of Dkk-1 on synovial angiogenesis.

Results

Dkk-1 expression was elevated in synovial fluids and synovial fibroblasts of RA patients. Treatment with various pro-inflammatory cytokines significantly promoted DKK-1 expression in RASF. The production of potent angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF was elevated, whereas the reverse results were found in the inhibitor groups. Silenced Dkk-1expression in RASF dampened capillary tube organization in both direct and indirect manners, resulting in restrained ERK, JNK, and p38 signaling pathway activation.

Conclusion

We concluded that Dkk-1 exacerbated the inflammation, cartilage erosion, and angiogenesis mediated by synovial fibroblasts in RA. Modulation of DKK-1 expression may facilitate development of novel strategies to control RA.

Key points

• Dkk-1 expression was elevated in synovial fluids and synovial fibroblasts of RA patients.

• Treatment with various pro-inflammatory cytokines significantly promoted DKK-1 expression.

• Silenced Dkk-1expression in RASF dampened capillary tube organization.

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Data availability

All data included in this study are available upon request by contact with the corresponding author.

Code availability

Not applicable.

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Funding

The work was supported by the National Natural Science Foundation of China (81771678, 81801617), Peking University People’s Hospital Research and Development Funds (RDH 2020–03).

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Author notes

  1. Li Zheng and Fanlei Hu contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, 100044, China

    Li Zheng, Fanlei Hu, Wenjie Bian, Yingni Li, Linqi Zhang, Lianjie Shi, Xiaoxu Ma, Yanying Liu, Xuewu Zhang & Zhanguo Li

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  1. Li Zheng
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Contributions

Concept and design: Xuewu Zhang, Yanying Liu, and Zhanguo Li.

Definition of intellectual content: Xuewu Zhang and Yanying Liu.

Literature search: Wenjie Bian and Yuqin Yang.

Experimental studies: Li Zheng and Fanlei Hu.

Supplementary experiments: Yanying Liu and Linqi Zhang.

Data acquisition: Lianjie Shi and Fanlei Hu.

Statistical analysis: Yingni Li and Wenjie Bian.

Manuscript preparation: Li Zheng and Fanlei Hu.

Manuscript editing and manuscript review: Xiaoxu Ma and Lianjie Shi.

Corresponding authors

Correspondence to Yanying Liu or Xuewu Zhang.

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Zheng, L., Hu, F., Bian, W. et al. Dickkopf-1 perpetuated synovial fibroblast activation and synovial angiogenesis in rheumatoid arthritis. Clin Rheumatol 40, 4279–4288 (2021). https://doi.org/10.1007/s10067-021-05766-9

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  • DOI: https://doi.org/10.1007/s10067-021-05766-9

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