Calcium, Phosphate And The Calcium-Sensing Receptor A Proinflammatory Combination In Rheumatoid Arthritis

Calcium and phosphate are necessary for the functionality of the organism and the cellular metabolism. In the form of hydroxyapatite, calcium and phosphate stabilize bone and teeth, but deposition of calcium phosphate in soft tissue or the vasculature can have devastating consequences. To prevent ectopic calcification, calcium and phosphate are stabilized by fetuin-A/alpha-2-HS-glycoprotein as non-crystalline, 60-100 nm-sized calciprotein particles (CPP) in extracellular fluids. An increase of the CPP concentration in the extracellular fluid beyond a certain threshold results in pro-inflammatory responses in monocytes and macrophages, which includes the activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome resulting in the release of interleukin-1 beta and interleukin-18. The release of pro-inflammatory cytokines as a result of increased CPPs is enhanced in rheumatoid arthritis (RA). The calcium-sensing receptor plays a major role in this mechanism by modulating the uptake (macropinocytosis) of CPPs and thereby increasing the pro-inflammatory potential. Bone erosion and subsequent release of calcium and phosphate during the etiopathology of RA can therefore aggravate the joint inflammation in this disease.