Osteoclastogenesis in Chronic Inflammation

Prof. Dr. Michael Seitz and PD Dr. Daniel Aeberli

Inflammation induced osteoclastogenesis is largely dependent on TNF. The mechanisms of anti-TNF response however is not known yet, particularly in terms of the migration of osteoclast precursor cells (OPCs), interaction with the endothelium and migration into the inflammation prone site, the joint. We hypothesize that the rapid and sustained downregulation of osteoclastogenesis by TNF inhibition (through infliximab) might be mediated not only by apoptosis induction of OPCs but also by reduced monocyte/OPC mobilization from bone marrow into peripheral tissues and by reduced attachment of OPCs to peripheral bone tissue and subsequently reduced differentiation into mature osteoclasts.

We have started to investigate this research hypothesis in a murine model of chronic antigen induced arthritis (AIA) in CCR2-RFP/CX3CR1-EGFP knock-in mice with and without intraperitoneal injection of anti-TNF/infliximab either before or at the onset of arthritic symptoms. Twophoton intravital microscopy (2PIVM) is used to image track sequences of transendothelial migration of endogenously labeled OPCs (and monocytes) into arthritic joints. Diapedesis of OPCs, attachement to bone matrix and differentiation into osteoclasts are investigated in serial sections of skull, femura and knees by histochemistry in mice sacrificed after 2PIVM. Recruitment of OPCs from bone marrow into peripheral tissues are monitored by FACS analysis of cellular components of bone marrow, peripheral blood and spleen.

This is a interdisciplinary research project supported by a grant from the Swiss National Foundation. Members of the research team are the followings: Prof.M.Seitz, S.Uster (PhD student), PD D.Aeberli (Department of Rheumatology, Clinical Immunology & Allergology, University Hospital of Bern), Prof.W.Hofstetter (Group of Bone Biology and Orthopaedic Research, Department of Clinical Research, University of Bern), Prof.B.Engelhardt, PD J.Stein (Theodor-Kocher Institute, University of Bern).