Acid‐Sensing Ion Channel 3 Deficiency Increases Inflammation but Decreases Pain Behavior in Murine Arthritis

Abstract

Objective Through its location on nociceptors, acid sensing ion channel 3 (ASIC3) is activated by decreases in pH and plays a significant role in musculoskeletal pain. We recently showed that decreases in pH activate ASIC3 located on fibroblast-like synoviocytes (FLS). Since FLS are key cells in the inflammatory process we tested if ASIC3-deficient mice with arthritis have altered inflammation and pain relative to controls. Methods Arthritis was induced by injection of a cocktail of anti-type II collagen antibodies induced collagen antibodyarthritis (CAIA). Inflammation and pain parameters in ASIC3−/− and ASIC3+/+ mice were assessed. Disease severity was measured with clinical arthritis scores, joint diameters, histological analysis of joints, and qPCR for synovial gene expression. Pain behaviors were measured by examining withdrawal thresholds of the joint and paw and by measuring physical activity levels in mice. Cell death was assessed with a Live/Dead assay in FLS in response to decreases in pH. Results Surprisingly, ASIC3−/− mice with CAIA demonstrated significantly increased joint inflammation, joint destruction and expression of IL-6, MMP-3 and MMP-13 in joint tissue compared to ASIC3+/+ mice. ASIC3+/+ FLS show enhanced cell death when exposed to pH 6.0 in the presence of interleukin-1β that is abolished in ASIC3−/− FLS. Despite enhanced disease severity, ASIC3−/− mice do not develop mechanical hypersensitivity of the paw and show greater levels of physical activity. Conclusion These data are consistent with the hypothesis that ASIC3 plays a protective role in inflammatory arthritis conditions by limiting inflammation through enhanced synoviocyte cell death to reduce disease severity and produce pain to reduce joint use.

Novel Insights into Acid-Sensing Ion Channels: Implications for Degenerative Diseases

“…Unexpectedly, joint inflammation and destruction were significantly enhanced in ASIC3 knockout mice with collagen antibody-induced arthritis, compared to wild type (WT) mice. Moreover, FLS exposed to pH 6.0 displayed enhanced cell death in the presence of IL-1, which was eliminated in ASIC3-/-FLS [82]. IL-1β upregulated ASIC3 mRNA and enhanced [Ca 2+ ]i, p-ERK, IL-6 and metalloproteinase mRNA as well as cell death in WT FLS exposed to pH 6.0.…”

Spinal Cord Stimulation Reduces Mechanical Hyperalgesia and Restores Physical Activity Levels in Animals with Noninflammatory Muscle Pain in a Frequency-Dependent Manner

“…75 Animals were placed in the box for 30 minutes, and their activity was videotaped and stored for later analysis. The computerized system reported a variety of automated measures based on a point on the animal's back located half-way between its nose and tail base.…”

The dichotomized role for acid sensing ion channels in musculoskeletal pain and inflammation

“…The passive collagen-induced arthritis model (CAIA) [23] is used to study rheumatoid arthritis since it produces distal and widespread inflammation and synovitis similar to rheumatoid arthritis. The CAIA model is also associated with enhanced sensitivity to nociceptive mechanical stimulation of cutaneous and deep tissue of the paw and reduced activity levels [35]. …”

“…In the CAIA model, ASIC3−/− mice develop mechanical hyperalgesia of the ankle, but not the adjacent paw as compared to wild-type mice [35]; thus following a similar pattern to that observed after muscle or joint inflammation. The reduced activity levels observed in the CAIA model are also attenuated in ASIC3−/− mice.…”

“…Despite the decreases in hyperalgesia, the ASIC3−/− mice show enhanced inflammation as measured by ankle joint thickness, arthritis scores, and histological changes after induction of CAIA [35]. Specifically, there is enhanced proteoglycan destruction, synovial thickness, bone destruction and inflammatory infiltrations in ASIC3−/− mice when compared to wildtype mice [35].…”