University of Oulu

Haidar O, O’Neill N, Staunton CA, Bavan S, O’Brien F, Zouggari S, Sharif U, Mobasheri A, Kumagai K and Barrett-Jolley R (2020) Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts. Front. Physiol. 11:226. doi: 10.3389/fphys.2020.00226

Pro-inflammatory cytokines drive deregulation of potassium channel expression in primary synovial fibroblasts

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Author: Haidar, Omar1; O’Neill, Nathanael1; Staunton, Caroline A.1;
Organizations: 1Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom
2Research Unit of Medical Imaging, Physics and Technology, University of Oulu, Oulu, Finland
3Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
4Department of Orthopedics and Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, Netherlands
5Versus Arthritis Centre for Sport, Exercise and Osteoarthritis Research, Queen’s Medical Centre, Nottingham, United Kingdom
6Department of Orthopaedic Surgery, Shiga University of Medical Science, Shiga, Japan
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 11.8 MB)
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Language: English
Published: Frontiers Media, 2020
Publish Date: 2020-07-07


The synovium secretes synovial fluid, but is also richly innervated with nociceptors and acts as a gateway between avascular joint tissues and the circulatory system. Resident fibroblast-like synoviocytes’ (FLS) calcium-activated potassium channels (KCa) change in activity in arthritis models and this correlates with FLS activation.

Objective: To investigate this activation in an in vitro model of inflammatory arthritis; 72 h treatment with cytokines TNFα and IL1β.

Methods: FLS cells were isolated from rat synovial membranes. We analyzed global changes in FLS mRNA by RNA-sequencing, then focused on FLS ion channel genes and the corresponding FLS electrophysiological phenotype and finally modeling data with ingenuity pathway analysis (IPA) and MATLAB.

Results: IPA showed significant activation of inflammatory, osteoarthritic and calcium signaling canonical pathways by cytokines, and we identified ∼200 channel gene transcripts. The large KCa (BK) channel consists of the pore forming Kcnma1 together with β-subunits. Following cytokine treatment, a significant increase in Kcnma1 RNA abundance was detected by qPCR and changes in several ion channels were detected by RNA-sequencing, including a loss of BK channel β-subunit expression Kcnmb1/2 and an increase in Kcnmb3. In electrophysiological experiments, there was a decrease in over-all current density at 20 mV without change in chord conductance at this potential.

Conclusion: TNFα and IL1β treatment of FLS in vitro recapitulated several common features of inflammatory arthritis at the transcriptomic level, including increase in Kcnma1 and Kcnmb3 gene expression.

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Series: Frontiers in physiology
ISSN: 1664-042X
ISSN-E: 1664-042X
ISSN-L: 1664-042X
Volume: 11
Article number: 226
DOI: 10.3389/fphys.2020.00226
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This study was funded by the European Union’s Seventh Framework Programme (EU FP7; grant agreement No. 305815), BBSRC (BB/N003020/1), The University of Liverpool, and King Abdulaziz University, Jeddah, Saudi Arabia.
Copyright information: © 2020 Haidar, O’Neill, Staunton, Bavan, O’Brien, Zouggari, Sharif, Mobasheri, Kumagai and Barrett-Jolley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.