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ASIC1a promotes the proliferation of synovial fibroblasts via the ERK/MAPK pathway

Abstract

Synovial hyperplasia, a profound alteration in the structure of synovial tissue, is the basis for cumulative joint destruction in rheumatoid arthritis (RA). It is generally accepted that controlling synovial hyperplasia can delay the progression of RA. As one of the most intensively studied isoforms of acid-sensing ion channels (ASICs), ASIC1a contributes to various physiopathologic conditions, including RA, due to its unique property of being permeable to Ca2+. However, the role and the regulatory mechanisms of ASIC1a in synovial hyperplasia are poorly understood. Here, rats induced with adjuvant arthritis (AA) and human primary synovial fibroblasts were used in vivo and in vitro to investigate the role of ASIC1a in the proliferation of RA synovial fibroblasts (RASFs). The results show that the expression of ASIC1a was significantly increased in synovial tissues and RASFs obtained from patients with RA as well as in the synovium of rats with AA. Moreover, extracellular acidification improved the ability of RASFs colony formation and increased the expression of proliferation cell nuclear antigen (PCNA) and Ki67, which was abrogated by the specific ASIC1a inhibitor psalmotoxin-1 (PcTX-1) or ASIC1a-short hairpin RNA (ASIC1a-shRNA), suggesting that extracellular acidification promotes the proliferation of RASFs by activating ASIC1a. In addition, the activation of c-Raf and extracellular signal-regulated protein kinases (ERKs) signaling was blocked with PcTX-1 or ASIC1a-shRNA and the proliferation of RASFs was further inhibited by the ERK inhibitor (U0126), indicating that ERK/MAPK signaling contributes to the proliferation process of RASFs promoted by the activation of ASIC1a. These findings gave us an insight into the role of ASIC1a in the proliferation of RASFs, which may provide solid foundation for ASIC1a as a potential target in the treatment of RA.

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Fig. 1: Pathological features and expression of ASIC1a in RA synovium.
Fig. 2: The high expression of ASIC1a in RA synovial fibroblasts.
Fig. 3: Effect of acidification on proliferation of RASFs.
Fig. 4: Effect of ASIC1a inhibition on the proliferation of RASFs.
Fig. 5: Effect of ASIC1a on the proliferation of RASFs.
Fig. 6: Effect of ASIC1a on the proliferation of synovial tissue in vivo.
Fig. 7: Effect of ASIC1a on the proliferation of RASFs through ERK/MAPK signaling.

Data availability

The data sets used during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant number 81873986).

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JT: Writing—review and editing. ZL: Data analysis. XQ: Performed study concept. YZ: Performed development methodology. YX: Review and revision of the paper. JS: Investigation and validation. XH: Supervision. SS: Investigation. XP: Supervision and editing. FC: provided technical and material support and editing. All authors read and approved the final paper.

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Correspondence to Feihu Chen.

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Tao, J., Lu, Z., Su, J. et al. ASIC1a promotes the proliferation of synovial fibroblasts via the ERK/MAPK pathway. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00636-z

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