The role of extracellular calcium and the calcium receptors CaSR and GPRC6A in the pathogenesis of rheumatoid arthritis

• Applicant: Professorin Dr. Manuela Rossol
• Subject Area: Rheumatology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 364979434

Rheumatoid arthritis is a chronic inflammatory joint disorder, which is characterized by the inflammation of the synovial membrane and bone destruction. Cell activation and cell necrosis occurs during inflammation and this leads to an increase in the concentration of calcium ions in the extracellular space. Bone erosions in RA patients might lead to additional local increased calcium concentrations. Monocytes/macrophages sense an increase in the extracellular calcium concentration by two G-protein coupled receptors, CaSR and GPRC6A. This leads to monocyte activation and the production of large amounts of Nlrp3-dependent cytokines IL-1 and IL-18, and other pro-inflammatory cytokines like TNF and IL-6.Aim of the project is to identify the role of an increased extracellular calcium concentration and the role of the calcium receptors CaSR and GPRC6A in the pathogenesis of RA. In preliminary work we were able to detect an increased calcium concentration in the synovial fluid of RA patients. Based on this result we want to study the calcium concentration in the synovial tissue, synovial fluid and the peripheral blood of RA patients and the bone marrow of arthritic mice. The participation of the calcium receptors CaSR and GPRC6A will be studied using knock-out mice and two different arthritis models (CAIA, CIA). Another goal of the project is the identification of functional consequences of an increased extracellular calcium concentration. We want to study the influence of extracellular calcium on the monocyte-dependent expansion of Th17 cells and on the differentiation of monocytes into macrophages. Extracellular calcium is able to chemotactically attract monocytes and we want to study if this process participates in the migration of monocytes in the synovial membrane.The project is intended to clarify the role of extracellular calcium and the role of the two calcium receptors CaSR and GPRC6A in the pathogenesis of RA and thereby identify a new therapeutic approach to modulate the proinflamamtory activation of monocytes/macrophages.

• DFG Programme: Research Grants