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Inhibition of Cdc37 Ameliorates Arthritis in Collagen-Induced Arthritis Rats by Inhibiting Synoviocyte Proliferation and Migration Through the ERK Pathway

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Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to synovial inflammation, pannus formation, cartilage damage, bone destruction, and ultimate disability. Fibroblast-like synoviocytes (FLS) are involved in the pathogenetic mechanism of RA. Cdc37 (cell division cycle protein 37) is regarded as a molecular chaperone involved in various physiological processes such as cell cycle progression, cell proliferation, cell signal transduction, tumorigenesis, and progression. However, the precise role of Cdc37 in the pathogenesis of rheumatoid arthritis (RA) remains uncertain. In our study, we found that Cdc37 expression was upregulated in human rheumatoid synovia in contrast with the normal group. Interestingly, Cdc37 activated the ERK pathway to promote RA-FLS proliferation and migration in vitro. Ultimately, in vivo experiments revealed that silencing of Cdc37 alleviated ankle swelling and cartilage destruction and validated the ERK signaling pathways in vitro findings. Collectively, we demonstrate that Cdc37 promotes the proliferation and migration of RA-FLS by activation of ERK signaling pathways and finally aggravates the progression of RA. These data indicated that Cdc37 may be a novel target for the treatment of RA.

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Data are available from the corresponding author on reasonable request.

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Funding

This work was supported by A Project of Nantong Science and Technology Program (JC2020015) and the Research Innovation Program for College Graduates of Jiangsu Province (KYCX20-2800).

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Authors and Affiliations

  1. Department of Orthopaedics, Medical School, Affiliated Hospital of Nantong University, Nantong University, No. 20 Xisi Road, Nantong, 226001, Jiangsu, China

    Weiwei Sun, Weijie Wu, Yunyi Nan, Youhua Wang & Hua Xu

  2. Department of Orthopaedics, Affiliated Nantong Hospital of Shanghai University, The Six People’s Hospital of Nantong, Jiangsu, 226001, Nantong, China

    Xingxing Mao & Weijie Wu

  3. Department of Nursing, Medical School, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China

    Chunxiang Xu

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Contributions

Weiwei Sun and Xingxing Mao performed the experiments. Weijie Wu and Yunyi Nan collected and analyzed the data. Hua Xu and Youhua Wang performed joint surgeries and provided synovial tissue. Weiwei Sun and Weijie Wu prepared the manuscript. Chunxiang Xu contributed to the conception of the study. All authors have read and approved the manuscript.

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Correspondence to Chunxiang Xu, Youhua Wang or Hua Xu.

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This study was approved by the institutional medical ethics committee of the Affiliated Hospital of Nantong University. Informed consent was acquired from all patients prior to surgery.

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Weiwei Sun, Weijie Wu, and Xingxing Mao contributed equally and should be regarded as co-first authors. 

Chunxiang Xu, Youhua Wang, and Hua Xu contributed equally and should be regarded as co-corresponding authors.

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Fig. S1 Immunohistochemical staining of negative controls in RA synovial tissues (TIF 3419 KB)

10753_2023_1789_MOESM2_ESM.tif

Fig. S2 RA-FLS were transfected with siRNA#2 and then stimulated by IL-1β or Tnfα (10ng/ml, 24 hours). The protein expression levels of p-ERK and ERK were measured by western blot. Experiments were repeated for three times, * compare with Con, P＜0.05 (TIF 1876 KB)

Fig. S3 The gatings of the flow cytometry analyses (TIF 2536 KB)

10753_2023_1789_MOESM4_ESM.tif

Fig. S4 H&E stained histological tissues of the main organs (heart, liver, spleen, lung, kidney) were collected from the different groups (TIF 144096 KB)

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Sun, W., Mao, X., Wu, W. et al. Inhibition of Cdc37 Ameliorates Arthritis in Collagen-Induced Arthritis Rats by Inhibiting Synoviocyte Proliferation and Migration Through the ERK Pathway. Inflammation 46, 1022–1035 (2023). https://doi.org/10.1007/s10753-023-01789-3

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