Caspase‐8 variant G regulates rheumatoid arthritis fibroblast‐like synoviocyte aggressive behavior

Ansalone, C. et al. (2022) Caspase‐8 variant G regulates rheumatoid arthritis fibroblast‐like synoviocyte aggressive behavior. ACR Open Rheumatology, 4(4), pp. 288-299. (doi: 10.1002/acr2.11384) (PMID:34963199) (PMCID:PMC8992463)

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Abstract

Objective: Fibroblast-like synoviocytes (FLS) play a pivotal role in rheumatoid arthritis (RA) by contributing to synovial inflammation and progressive joint damage. An imprinted epigenetic state is associated with the FLS aggressive phenotype. We identified CASP8 (encoding for caspase-8) as a differentially marked gene and evaluated its pathogenic role in RA FLSs. Methods: RA FLS lines were obtained from synovial tissues at arthroplasty and used at passage 5-8. Caspase-8 was silenced using small interfering RNA, and its effect was determined in cell adhesion, migration and invasion assays. Quantitative reverse transcription PCR and western blot were used to assess gene and protein expression, respectively. A caspase-8 selective inhibitor was used determine the role of enzymatic activity on FLS migration and invasion. Caspase-8 isoform transcripts and epigenetic marks in FLSs were analyzed in FLS public databases. Crystal structures of caspase-8B and G were determined. Results: Caspase-8 deficiency in RA FLSs reduced cell adhesion, migration, and invasion independent of its catalytic activity. Epigenetic and transcriptomic analyses of RA FLSs revealed that a specific caspase-8 isoform, variant G, is the dominant isoform expressed (~80% of total caspase-8) and induced by PDGF. The crystal structures of caspase-8 variant G and B were identical except for a unique unstructured 59 amino acid N-terminal domain in variant G. Selective knockdown of caspase-8G was solely responsible for the effects of caspase-8 on calpain activity and cell invasion in FLS. Conclusion: Blocking caspase-8 variant G could decrease cell invasion in diseases like RA without the potential deleterious effects of nonspecific caspase-8 inhibition.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ansalone, Dr Cecilia
Authors: Ansalone, C., Ainsworth, R. I., Nygaard, G., Ai, R., Prideaux, E. B., Hammaker, D., Perumal, N. B., Weichert, K., Tung, F., Kodandapani, L., Sauder, J. M., Mertsching, E. C., Benschop, R. J., Boyle, D. L., Wang, W., and Firestein, G. S.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:ACR Open Rheumatology
Publisher:Wiley
ISSN:2578-5745
ISSN (Online):2578-5745
Published Online:28 December 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in ACR Open Rheumatology 4(4): 288-299
Publisher Policy:Reproduced under a Creative Commons License

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