Dataset Information

Snail regulation in fibroblast-like synoviocytes by a histone deacetylase or glycogen synthase kinase inhibitor affects cell proliferation and gene expression.

ABSTRACT:

Background

Snail has been linked to the pathogenesis of rheumatoid arthritis (RA). We plan to investigate the regulation of Snail in response to TNF-α, histone acetylation, and glycogen synthase kinase-3 (GSK)-3 inhibition in fibroblast-like synoviocytes (FLSs).

Methods

FLSs from rats with collagen-induced arthritis (CIA) were collected and treated with TNF-α alone or a combination with trichostatin A (TSA), a pan-histone deacetylase inhibitor and lithium chloride (LiCl), a glycogen synthase kinase-3 (GSK)-3 inhibitor.

Results

We demonstrated for the first time that nuclear expression of Snail in FLSs from rats with CIA was correlated with the levels of extracellular TNF-α and acetylation status. Cell proliferation and viability of CIA FLSs were reduced in response to TSA treatment and short-hairpin RNA specific to Snail. LiCl treatment increased Snail and cadherin-11 (Cad-11) expression in CIA FLSs.

Conclusion

We suggested from this study that targeting TNF-α-histone deacetylase-Snail signaling axis or the Wnt signaling pathway in FLSs might provide therapeutic interventions for the treatment of RA in the future.

SUBMITTER: Shen PC

PROVIDER: S-EPMC8478242 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:HAPLN1 maintains aggregation and the binding activity of extracellular matrix (ECM) molecules (such as hyaluronic acid and proteoglycan) to stabilize the macromolecular structure of the ECM. An increase in HAPLN1 expression is observed in a few types of musculoskeletal diseases including rheumatoid arthritis (RA); however, its functions are obscure. This study examined the role of HAPLN1 in determining the viability, proliferation, mobility, and pro-inflammatory phenotype of RA- fibroblast-like synoviocytes (RA-FLSs) by using small interfering RNA (siHAPLN1), over-expression vector (HAPLN1OE), and a recombinant HAPLN1 (rHAPLN1) protein. HAPLN1 was found to promote proliferation but inhibit RA-FLS migration. Metformin, an AMPK activator, was previously found by us to be able to inhibit FLS activation but promote HAPLN1 secretion. In this study, we confirmed the up-regulation of HAPLN1 in RA patients, and found the positive relationship between HAPLN1 expression and the AMPK level. Treatment with either si-HAPLN1 or HAPLN1OE down-regulated the expression of AMPK-ɑ gene, although up-regulation of the level of p-AMPK-ɑ was observed in RA-FLSs. si-HAPLN1 down-regulated the expression of proinflammatory factors like TNF-ɑ, MMPs, and IL-6, while HAPLN1OE up-regulated their levels. qPCR assay indicated that the levels of TGF-β, ACAN, fibronectin, collagen II, and Ki-67 were down-regulated upon si-HAPLN1 treatment, while HAPLN1OE treatment led to up-regulation of ACAN and Ki-67 and down-regulation of cyclin-D1. Proteomics of si-HAPLN1, rHAPLN1, and mRNA-Seq analysis of rHAPLN1 confirmed the functions of HAPLN1 in the activation of inflammation, proliferation, cell adhesion, and strengthening of ECM functions. Our results for the first time demonstrate the function of HAPLN1 in promoting the proliferation and pro-inflammatory phenotype of RA-FLSs, thereby contributing to RA pathogenesis. Future in-depth studies are required for better understanding the role of HAPLN1 in RA.