Investigation of the roles of acid sensing proteins in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterised by chronic joint inflammation, which is generally associated with destruction of articular cartilage and bone. Inflammatory cytokines, such as tumour necrosis factor (TNF), promote the up-regulation of proteases that degrade components of the extracellular matrix in cartilage and bone. Chronic joint inflammation results in reduced concentrations of oxygen (hypoxia). Hypoxic conditions cause anaerobic respiration and lactic acid build-up in synoviocytes, which are the cells that line articular joints. Acid-sensing proteins respond to these acidic conditions in the extracellular space of joints. We hypothesized that acid-sensing proteins play a critical role in the development and pathology of RA through diverse signalling and cellular functional responses. Identification of the exact signalling mechanisms and expression of acid-sensing proteins may facilitate development of effective management options for patients with RA.
In this study, by using immunohistochemistry paraffin protocol (IHC-P) and real-time polymerase chain reaction, we demonstrated that four acid-sensing proteins were expressed at variable levels in synovial biopsies from RA patients and at the messenger ribonucleic acid (mRNA) level in RA fibroblast-like synoviocytes (FLS). Expression levels of these proteins were slightly induced at the mRNA level by the inflammatory cytokine TNF. Importantly, acidic conditions that mimicked the inflamed synovial joint in RA also resulted in a significant increase in matrix metalloproteinase (MMP)-1 and MMP-9, whereas migration activity of RA FLS was reduced. Furthermore, ASIC3 and TRPV1 inhibition resulted in a significant down-regulation of MMP-1 and -9 at mRNA level in RA-FLS under low pH.