Background: Rheumatoid arthritis is an inflammatory disease marked by intraarticular decreases in pH, aberrant hyaluronan regulation, and destruction of bone and cartilage. Acid sensing ion channels (ASICs) are the primary acid sensors in the nervous system, particularly in sensory neurons and are important in nociception. We recently discovered ASIC3 in synoviocytes, non-neuronal joint cells critical to the inflammatory process.
Objectives: To investigate the role of ASIC3 in joint tissue, specifically the relationship between ASIC3 and hyaluronan, and the response to decreased pH. Methods: We utilized histochemical methods to compare morphology, hyaluronan expression and ASIC3 expression in ASIC3+/+ and ASIC3-/- mouse knee joints. We used isolated fibroblast-like synoviocytes (FLS) to examine hyaluronan release and intracellular calcium in response to decreases in pH.
Results: In tissue sections from ASIC3+/+ mice, ASIC3 localized to articular cartilage, growth plate, meniscus, and Type B synoviocytes. In cultured FLS, ASIC3 mRNA and protein was also expressed. In FLS cultures, pH 5.5 increased hyaluronan release in ASIC3+/+ FLS, but not ASIC3-/- FLS. In FLS from ASIC3+/+ mice, approximately 50% of cells (25/53) increased intracellular calcium while only 24% (14/59) showed an increase in ASIC3-/- FLS. Of the cells that responded to pH 5.5, there was significantly less intracellular calcium increases in ASIC3-/- FLS compared to ASIC3+/+ FLS.
Conclusion: ASIC3 may serve as a pH sensor in synoviocytes, and be important for modulation of expression of hyaluronan within joint tissue.