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Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium

Weiyi Gong12, Sandra J Kolker2, Yuriy Usachev3, Roxanne Y Walder2, David L Boyle4, Gary S Firestein4 and Kathleen A Sluka2*

Author Affiliations

1 Department of Anesthesiology, Fujian Medical University Union Hospital, Fuzhou City, Fujian, China

2 Department of Physical Therapy and Rehabilitation Science, Pain Research Program, University of Iowa Carver College of Medicine, 500 Newton Road, 1-248 Medical Education Building, Iowa City, IA 52242, USA

3 Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA

4 Division of Rheumatology, Allergy and Immunology, University of California San Diego School of Medicine, La Jolla, CA, USA

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Arthritis Research & Therapy 2014, 16:R121  doi:10.1186/ar4577

Published: 12 June 2014



Acid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS).


Experiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca2+]i, mitogen activated kinase (MAP kinase) expression, and cell death. [Ca2+]i was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay.


Acidic pH increased [Ca2+]i and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca2+]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca2+]i, p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca2+]i and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS.


Decreased pH activates ASIC3 resulting in increased [Ca2+]i, and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca2+]i and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage.