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

Tao, Jingjing; Zheng, Liduan; Su, Jingwen; Qian, Xuewen; Zhang, Yihao; Xu, Yayun; Song, Sujing; Hang, Xiaoyu; Peng, Xiaoqing; Chen, Feihu

doi:10.1038/s41374-021-00636-z

Cited by 7 publications

(3 citation statements)

References 45 publications

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“…Cyclin D1 is G1/s-specific Cyclin-D1, which is necessary for the progression of cell cycle from G1 to S phase. PCNA is closely related to cell DNA synthesis and plays an important role in the initiation of cell proliferation, and is a good indicator to reflect the state of cell proliferation (Converse and Thomas 2021 ; Tao et al 2021 ). The results showed that the increase expression of Cyclin D1 and PCNA in RA-FLSs were closely associated with increased cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Deng

Wang

et al. 2022

Mol Med

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Background Hypoxia is one of the important characteristics of synovial microenvironment in rheumatoid arthritis (RA), and plays an important role in synovial hyperplasia. In terms of cell survival, fibroblast-like synovial cells (FLSs) are relatively affected by hypoxia. In contrast, fibroblast-like synovial cells from patients with RA (RA-FLSs) are particularly resistant to hypoxia-induced cell death. The purpose of this study was to evaluate whether fibroblast-like synovial cells in patients with osteoarthritis (OA-FLSs) and RA-FLSs have the same adaptation to hypoxia. Methods CCK-8, flow cytometry and BrdU were used to detect the proliferation of OA-FLSs and RA-FLSs under different oxygen concentrations. Apoptosis was detected by AV/PI, TUNEL and Western blot, mitophagy was observed by electron microscope, laser confocal microscope and Western blot, the state of mitochondria was detected by ROS and mitochondrial membrane potential by flow cytometry, BNIP3 and HIF-1α were detected by Western blot and RT-qPCR. The silencing of BNIP3 was achieved by stealth RNA system technology. Results After hypoxia, the survival rate of OA-FLSs decreased, while the proliferation activity of RA-FLSs further increased. Hypoxia induced an increase in apoptosis and inhibition of mitophagy in OA-FLSs, but not in RA-FLSs. Hypoxia led to a more lasting adaptive response. RA-FLSs displayed a more significant increase in the expression of genes transcriptionally regulated by HIF-1α. Interestingly, they showed higher BNIP3 expression than OA-FLSs, and showed stronger mitophagy and proliferation activities. BNIP3 siRNA experiment confirmed the potential role of BNIP3 in the survival of RA-FLSs. Inhibition of BNIP3 resulted in the decrease of cell proliferation, mitophagy and the increase of apoptosis. Conclusion In summary, RA-FLSs maintained intracellular redox balance through mitophagy to promote cell survival under hypoxia. The mitophagy of OA-FLSs was too little to maintain the redox balance of mitochondria, resulting in apoptosis. The difference of mitophagy between OA-FLSs and RA-FLSs under hypoxia is mediated by the level of BNIP3 expression.

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Section: Discussionmentioning

confidence: 99%

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Deng

Wang

et al. 2022

Mol Med

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“…Indeed, it has been shown that the opening of ASIC1a channels activates Ras-related C3 botulinum toxin substrate 1 and promotes RA synovial cell invasion [ 48 ]. In addition, recent evidence has also demonstrated that ASIC1a promotes the proliferation of RA FLS cells through the ERK/MAPK and NFAT signaling [ 49 , 50 ]. This available evidence suggests that ASIC1a plays a toxic role in synovial inflammation, and the proper blockade of ASIC1a channels in the synovium may slow the progression of RA synovitis.…”

Section: Acid-sensitive Ion Channels (Asic)mentioning

confidence: 99%

Calcium-Permeable Channels Cooperation for Rheumatoid Arthritis: Therapeutic Opportunities

Liang

Yin

et al. 2022

Biomolecules

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Rheumatoid arthritis is a common autoimmune disease that results from the deposition of antibodies–autoantigens in the joints, leading to long-lasting inflammation. The main features of RA include cartilage damage, synovial invasion and flare-ups of intra-articular inflammation, and these pathological processes significantly reduce patients’ quality of life. To date, there is still no drug target that can act in rheumatoid arthritis. Therefore, the search for novel drug targets has become urgent. Due to their unique physicochemical properties, calcium ions play an important role in all cellular activities and the body has evolved a rigorous calcium signaling system. Calcium-permeable channels, as the main operators of calcium signaling, are widely distributed in cell membranes, endoplasmic reticulum membranes and mitochondrial membranes, and mediate the efflux and entry of Ca2+. Over the last century, more and more calcium-permeable channels have been identified in human cells, and the role of this large family of calcium-permeable channels in rheumatoid arthritis has gradually become clear. In this review, we briefly introduce the major calcium-permeable channels involved in the pathogenesis of RA (e.g., acid-sensitive ion channel (ASIC), transient receptor potential (TRP) channel and P2X receptor) and explain the specific roles and mechanisms of these calcium-permeable channels in the pathogenesis of RA, providing more comprehensive ideas and targets for the treatment of RA.

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“…The isolation and culture of SFs were performed as described previously [20,21]. Briefly, fresh synovium was cut into small pieces of approximately 1 mm 3 in a sterile environment.…”

Section: Isolation and Culture Of Synovial Fibroblasts (Sfs)mentioning

confidence: 99%

Inhibition of NUCB2 suppresses the proliferation, migration, and invasion of rheumatoid arthritis synovial fibroblasts from patients with rheumatoid arthritis in vitro

Zhang

et al. 2022

J Orthop Surg Res

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Rheumatoid arthritis (RA) is an autoimmune polyarthritis in which synovial fibroblasts (SF) play a major role in cartilage and bone destruction through tumorlike proliferation, migration, and invasion. Nesfatin-1, an 82-amino-acid-long peptide discovered by Oh-I in 2006, is derived from the precursor protein nucleobindin-2 (NUCB2). NUCB2/nesfatin-1 promotes cell proliferation, migration, and invasion in various tumors. We have previously shown that increased nesfatin-1 levels in the synovium may be associated with disease severity in patients with RA. However, the effect of NUCB2 on the tumorlike transformation of RASF has not yet been reported. The expression of NUCB2 mRNA in the synovium of RA and non-RA patients was further confirmed using three individual datasets from the NCBI GEO database. Gene set enrichment analysis (GSEA) was employed to explore the association between NUCB2 mRNA and RA-related gene signatures or signaling pathways in the GSE77298 dataset. Cell proliferation, migration, and invasion abilities were determined using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and transwell assays, respectively. The results showed that the levels of NUCB2 mRNA in the synovium were significantly elevated in patients with RA. Moreover, GSEA showed that high expression of NUCB2 mRNA was related to gene signatures, including those involved in the cell cycle, DNA replication, extracellular matrix–receptor interaction, and focal adhesion. Furthermore, the results of CCK-8 and EdU assays indicated that inhibition of NUCB2 markedly repressed RASF proliferation. Additionally, the results of wound healing and transwell assays demonstrated that inhibition of NUCB2 significantly suppressed the migratory and invasive abilities of RASFs. Our findings are the first to demonstrate that the inhibition of NUCB2 suppresses the proliferation, migration, and invasion of RASFs in vitro.

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

Cited by 7 publications

References 45 publications

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Calcium-Permeable Channels Cooperation for Rheumatoid Arthritis: Therapeutic Opportunities

Inhibition of NUCB2 suppresses the proliferation, migration, and invasion of rheumatoid arthritis synovial fibroblasts from patients with rheumatoid arthritis in vitro

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