Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis

Kathleen A Sluka; Lynn A Rasmussen; Meghan M Edgar; James M O'Donnell; Roxanne Y Walder; Sandra J Kolker; David L Boyle; Gary S Firestein

doi:10.1002/art.37862

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Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis

Journal article

Open access

Peer reviewed

Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis

Kathleen A Sluka, Lynn A Rasmussen, Meghan M Edgar, James M O'Donnell, Roxanne Y Walder, Sandra J Kolker, David L Boyle and Gary S Firestein

Arthritis and rheumatism, Vol.65(5), pp.1194-1202

05/2013

DOI: 10.1002/art.37862

PMCID: PMC3636153

PMID: 23335302

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Abstract

Through its location on nociceptors, acid-sensing ion channel 3 (ASIC-3) is activated by decreases in pH and plays a significant role in musculoskeletal pain. We recently showed that decreases in pH activate ASIC-3 located on fibroblast-like synoviocytes (FLS), which are key cells in the inflammatory process. The purpose of this study was to test whether ASIC-3-deficient mice with arthritis have altered inflammation and pain relative to controls. Collagen antibody-induced arthritis (CAIA) was generated by injection of an anti-type II collagen antibody cocktail. Inflammation and pain parameters in ASIC-3(-/-) and ASIC-3(+/+) mice were assessed. Disease severity was assessed by determining clinical arthritis scores, measuring joint diameters, analyzing joint histology, and assessing synovial gene expression by quantitative polymerase chain reaction analysis. Cell death was assessed with a Live/Dead assay of FLS in response to decreases in pH. Pain behaviors in the mice were measured by examining withdrawal thresholds in the joints and paws and by measuring their physical activity levels. Surprisingly, ASIC-3(-/-) mice with CAIA demonstrated significantly increased joint inflammation, joint destruction, and expression of interleukin-6 (IL-6), matrix metalloproteinase 3 (MMP-3), and MMP-13 in joint tissue as compared to ASIC-3(+/+) mice. ASIC-3(+/+) FLS showed enhanced cell death when exposed to pH 6.0 in the presence of IL-1β, which was abolished in ASIC-3(-/-) FLS. Despite enhanced disease severity, ASIC-3(-/-) mice did not develop mechanical hypersensitivity of the paw and showed greater levels of physical activity. Our findings are consistent with the hypothesis that ASIC-3 plays a protective role in the inflammatory arthritides by limiting inflammation through enhanced synoviocyte cell death, which reduces disease severity, and through the production of pain, which reduces joint use.

Hindlimb

Matrix Metalloproteinases - genetics

Male

Arthritis, Rheumatoid - complications

Joints - physiopathology

Hyperalgesia

Arthritis, Experimental - pathology

Behavior, Animal

Cell Death

Synovitis - etiology

Pain - etiology

Female

Interleukin-6 - metabolism

Arthritis, Rheumatoid - physiopathology

Joints - metabolism

Severity of Illness Index

Gene Expression

Arthritis, Experimental - physiopathology

Interleukin-6 - genetics

Cell Survival

Mice, Inbred C57BL

Joints - pathology

Arthritis, Experimental - complications

Pain - pathology

Arthritis, Rheumatoid - pathology

Mice, Knockout

Synovitis - pathology

Acid Sensing Ion Channels - deficiency

Synovitis - physiopathology

Animals

Pain - physiopathology

Pain Threshold

Mice

Matrix Metalloproteinases - metabolism

Pain Measurement

Details

Title: Subtitle: Acid-sensing ion channel 3 deficiency increases inflammation but decreases pain behavior in murine arthritis
Creators: Kathleen A Sluka - Department of Physical Therapy and Rehabilitation Science, University of Iowa Carver College of Medicine, Iowa City 52242, USA. kathleen-sluka@uiowa.edu
Lynn A Rasmussen
Meghan M Edgar
James M O'Donnell
Roxanne Y Walder
Sandra J Kolker
David L Boyle
Gary S Firestein
Resource Type: Journal article
Publication Details: Arthritis and rheumatism, Vol.65(5), pp.1194-1202
DOI: 10.1002/art.37862
PMID: 23335302
PMCID: PMC3636153
NLM abbreviation: Arthritis Rheum
ISSN: 0004-3591
eISSN: 1529-0131
Publisher: Wiley; United States
Grant note: R01 AR053509 / NIAMS NIH HHS
Language: English
Date published: 05/2013
Academic Unit: Iowa Neuroscience Institute; Nursing; Anesthesia; Physical Therapy and Rehabilitation Science; Neuroscience and Pharmacology
Record Identifier: 9984040289002771

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49 Times Cited - Web of Science