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Osteoclastogenesis and chronic inflammatory rheumatic disorders

English title Osteoclastogenesis and chronic inflammatory rheumatic disorders
Applicant Seitz Michael
Number 119905
Funding scheme Project funding (Div. I-III)
Research institution Universitätsklinik für Rheumatologie, Immunologie und Allergologie Inselspital
Institution of higher education University of Berne - BE
Main discipline Clinical Immunology and Immunopathology
Start/End 01.12.2008 - 30.11.2011
Approved amount 180'000.00
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All Disciplines (2)

Discipline
Clinical Immunology and Immunopathology
Diseases of Bones and Joints

Keywords (2)

osteoclastogenesi; chronic inflammation

Lay Summary (English)

Lead
Lay summary
Osteoclastogenesis and chronic inflammatory disorders Background: Anti-TNFa treatment was shown to reduce the frequency of osteoclast precursor cells (OCPs) and to stop structural joint damage in spondarthritis as well as in rheumatoid arthritis (RA) patients. Aim: This research proposal is therefore designed to investigate the following hypothesis :Osteoclastogenesis induced by inflammation is largely dependent on TNF a. The rapid initial downregulation of osteoclastogenesis by TNFa inhibition (infliximab) does occur by the induction of apoptosis in a subpopulation of highly susceptible inflammatory monocytes/OCPs in RA, whereas the sustained longterm inhibition of OCPs both in RA and AS is due to impaired monocyte/OCP recruitment from bone marrow or to changes in the OCP/T-cell interaction that render OCPs less sensitive to osteoclastogenic stimuli. This hypothesis will be examined in a threefold experimental design: 1) By in vitro experiments with normal human blood monocytes from buffy coats to investigate the evolution of inflammatory and non-inflammatory immunophenotypes of monocytes/OCPs before and after exposure to stimulation with inflammatory cytokines and to test the sensitivity of monocyte/OCP subpopulations towards infliximab in vitro regarding induction of apoptosis. 2) By ex vivo experiments with mouse bone marrow monocytes/macrophages from normal and TNF receptor p55/p75 deficient mice to investigate the TNFa-dependency of cytokine-induced osteoclast activation and 3) by ex vivo experiments with co-cultures of subpopulations of human blood and bone marrow- derived monocytes/OCPs as well as of blood T lymphocytes from RA and AS patients in a prospective clinical study before and after 6 months of infliximab treatment in vivo. Significance of the project : In particular, we expect a better understanding of 1) at what level TNFa-blockers do interfere with inflammation-mediated development from bone marrow and blood precursor cells (recruitment and survival) into bone resorbing osteo- clasts (maturation and activation) and 2) of what the impact of TNFa neutralisation on the interplay between the immune system, its soluble products (RANKL, macrophage migration inhibiting factor/MIF, IL-17) and bone in chronic inflammatory rheumatic diseases may be.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the American College of Rheumatology 04.11.2011 Chicago
European Calcified Tissue Society - PhD Student Workshop 01.09.2011 Ljubljana
European Calcified Tissue Society 07.05.2011 Athen
Tagung der Swiss Bone and Mineral Society 07.04.2011 Bern


Associated projects

Number Title Start Funding scheme
138459 Osteoklastogenese und chronisch entzündliche rheumatische Erkrankungen 01.03.2012 Project funding (Div. I-III)
138459 Osteoklastogenese und chronisch entzündliche rheumatische Erkrankungen 01.03.2012 Project funding (Div. I-III)

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