Molecular mechanisms of Th17 T cell effector function on cartilage and bone matrix destruction in rheumatoid arthritis (RA) and its modulation via osteopontin

• Antragstellerin: Professorin Dr. Sabine Blaschke-Steinbrecher
• Fachliche Zuordnung: Rheumatologie
• Förderung: Förderung von 2010 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 169415136

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease of still unknown etiology leading to progressive cartilage and bone destruction by chronic synovitis. Functional disability and increased mortality as long-term consequences of RA account for an enormous impact on healthcare economics.Recent studies demonstrated that a novel CD4+ T cell lineage termed Th17 cells play an important role in RA pathogenesis by production of its signature cytokine interleukin-17 (IL-17). In experimental mouse arthritis models, IL-17/Th17 cells were shown to promote both chronic synovial inflammation and cartilage as well as bone destruction. However, due to newly identified significant differences between murine and human IL-17/Th17 cell function, molecular mechanisms of IL-17-induced matrix degradation in human RA still have to be elucidated.Our previous studies reveal that human articular chondrocytes, chondrogenic progenitor cells as well as monocyte-derived osteoclasts isolated from RA patients express the IL-17 receptors IL-17RA and -RC.We thus hypothesize that IL-17/Th17 T cells may support matrix degradation in human RA in part by direct activation of the IL-17 receptor on RA chondrocytes and osteoclasts. Furthermore, we suppose that osteopontin (OPN) which has recently been identified as a potent stimulus of IL-17 production in Th17 T cells may modulate the process of IL-17-induced matrix degradation in RA.It is the goal of our project to analyze the molecular mechanisms of human IL-17/Th17 function on bone remodelling in RA and to characterize its modulation by OPN. Results of the project will promote the identification and clear definition of novel therapeutic target molecules as an essential prerequisite for the development of innovative treatment strategies in RA.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1468: Osteoimmunology - IMMUNOBONE - A Program to Unravel the Mutual Interactions between the Immune System and Bone
• Beteiligte Personen: Privatdozent Dr. Alexander W. Beham; Professor Dr. Nicolai Miosge