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Osteoklastogenese und chronisch entzündliche rheumatische Erkrankungen

English title Osteoclastogenesis and chronic inflammatory rheumatic diseases
Applicant Seitz Michael
Number 138459
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 Physiology : other topics
Start/End 01.03.2012 - 30.09.2015
Approved amount 311'000.00
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Keywords (4)

trafficking of osteoclast progenitor cells; tumor necrosis factor alpha; animal model of arthritis; in vivo cell imaging

Lay Summary (English)

Lead
Lay summary

mediated osteoclastogenesis in chronic inflammatory arthritis.

mechanisms by which therapeutic neutralization of TNF can inhibit cytokine -

on this process will be tightly monitored. Thereby, we expect to elucidate the

mammal that suffers from chronic inflammation and the effects of anti-TNF treatment

CX3CR1-EGFP knock-in arthritic mouse model to follow the fate of OPCs in a living

of intravital microscopy will be applied for the first time in a hTNF-transgenic x

mouse model of chronic arthritis. To this purpose, newly developed imaging techniques

of osteoclast precursor cells (OPCs) from bone marrow into peripheral tissues in a

project lies on the elucidation of TNF -mediated kinetics of mobilization and migration

synovial inflammation, osteoclastogenesis and joint destruction. The focus of this

basic research in chronic inflammatory diseases characterized by TNF -driven

Significance of the project: The proposed research combines expertise of clinical and

structure and mass will be visualized by MicroCT analysis of calvaria bone.

quantitative histomorphometrical analysis, and consequential changes in bone

IVM. Finally, changes in osteoclast number and density will be assessed by

will be determined both by conventional intravital imaging (IVM) and by two photon

established spontaneous arthritis with and without anti-TNF (infliximab) treatment

these cells into peripheral tissues in preclinical states and in distinct states of clinically

and by immunohisto-chemistry respectively. Furthermore, the kinetics of trafficking of

frequency of OPCs in bone marrow, circulation, spleen and inflamed joints by FACS

exhibit endogenously labeled OPCs. Their offsprings will be investigated for the

be crossed or not crossed with CX3CR1-EGFP knock-in (heterozygous) mice that

Experimental design: hTNF -transgenic mice that develop spontaneous arthritis will

bone tissue and subsequently reduced differentiation into mature osteoclasts.

bone marrow into peripheral tissues and by reduced attachment of OCPs to peripheral

mediated by apoptosis of OPCs but also by reduced monocyte/OPC mobilization from

downregulation of osteoclastogenesis by TNF inhibition (infliximab) is not only

osteoclastogenesis is largely dependent on TNF . The rapid and sustained

osteoclasts at inflammatory sites could occur. Hypothesis: Inflammation induced

OPCs into inflammatory sites and reduced differentiation of OPCs into bone resorbing

induction also downregulation of mobilization from bone marrow and of trafficking of

TNF producing) can be differentiated into active osteoclasts. Besides apoptosis

monocyte subpopulation that in contrast to CD11b+/CD16+ monocytes (inflammatory

apoptosis induction of OPCs and a concomitant decline of CD11b+/CD163+ circulating

differentiated in vitro under the influence of M-CSF and RANKL was associated with

to AS patients. The initial marked inhibition of bone resorption by OPCs that were

serum osteocalcin levels and a relative decrease of collagen crosslinks in RA compared

reduction of clinical disease activity in both patients cohorts and with an increase of

compared to patients with ankylosing spondylitis. This inhibition coincided with

resorption by OPCs in both diseases but did occur faster and more markedly in RA

monoclonal antibody to human TNF ) resulted in a strong reduction of bone

and in spondarthritis patients as well. Blocking of TNF with infliximab (chimeric

precursor cells (OPCs) and tos top structural joint damage in rheumatoid arthritis (RA)

Background: Anti-TNF treatment was shown to reduce the frequency of osteoclast

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
TNFα blockade mediates bone protection in antigen-induced arthritis by reducing osteoclast precursor supply
Uster Stephanie, Coelho Fernanda Matos, Aeberli Daniel, Stein Jens V., Hofstetter Wilhelm, Engelhardt Britta, Seitz Michael (2018), TNFα blockade mediates bone protection in antigen-induced arthritis by reducing osteoclast precursor supply, in Bone, 107, 56-65.
Regulation of peripheral classical and non-classical monocytes on infliximab treatment in patients with rheumatoid arthritis and ankylosing spondylitis
daniel aeberli richrd k. kamgang deepak balani willy hofstetter peter m. villiger michael seitz (2016), Regulation of peripheral classical and non-classical monocytes on infliximab treatment in patients with rheumatoid arthritis and ankylosing spondylitis, in RMD Open, 2016; 2(e000079), 1-5.
TNFalpha blockade mediates bone protection in antigen-induced arthritis by reducing osteoclast precursor supply
Uster Stephanie, TNFalpha blockade mediates bone protection in antigen-induced arthritis by reducing osteoclast precursor supply, in Elsevier, (107), 56-65.

Collaboration

Group / person Country
Types of collaboration
Dr.M.R.Ransohoff, Department of Neurosciences, Lerner Research Center, Cleveland United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Dr. F.I.Charo, Gladstone Institute of Cardiovascular Research, San Francisco United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EULAR Meeting Poster Effect s of anti-TNF therapy on the recruitment and availability of osteoclast precursors in a model of rheumatoid arthritis 10.06.2015 Rom, Italy Uster Stephanie; Seitz Michael; Hofstetter Wilhelm; Engelhardt Britta; Aeberli Daniel; Stein Jens Volker;
Worl Immune Regulation Meeting Poster Effect of anti-TNF therapy on the recruitment and availability of osteoclast precursors in a murine model of Rheumatoid Arthritis 19.02.2015 Davos, Switzerland Seitz Michael; Engelhardt Britta; Uster Stephanie; Aeberli Daniel; Stein Jens Volker; Hofstetter Wilhelm;
ProDoc Cell Migration Retreat Talk given at a conference Effect of anti-TNF therapy on the recruitment and availability of osteoclast precursors in a murine model of Rheumatoid Arthritis 11.02.2015 Weggis, Switzerland Uster Stephanie; Aeberli Daniel; Seitz Michael; Hofstetter Wilhelm; Engelhardt Britta; Stein Jens Volker;
GCB Symposium, Graduate School, University of Bern Talk given at a conference Effect of anti-TNF therapy on the recruitment and availability of osteoclast precursors in amurine model of Rheumatoid Arthritis 28.01.2015 Bern, Switzerland Uster Stephanie;
Pro Doc Cell migration Meeting Talk given at a conference Trafficking and Differentiation of Osteoclast Precursor Cells in a Murine Model of Rheumatoid Arthritis 11.06.2014 Bellinzona, Switzerland Uster Stephanie;
12th International Summer School, University of Bern Poster Trafficking and Differentiation of Osteoclast Precursor Cells in a Murine Moedel of Rheumatoid Arthritis 05.08.2013 Bern, Switzerland Aeberli Daniel; Uster Stephanie; Seitz Michael; Hofstetter Wilhelm; Engelhardt Britta; Stein Jens Volker;
ProDoc Cell migration Meeting Talk given at a conference Trafficking and Differentiation of Osteoclast Precursor Cells in a Murine Model of Rheumatoid Arthritis 02.07.2013 Fribourg, Switzerland Uster Stephanie;
11th International Summer School, University of Bern Poster Trafficking and Differentiation of Osteoclast Precursor Cells in a Murine Model of Rheumatoid Arthritis 13.08.2012 Bern, Switzerland Uster Stephanie;


Associated projects

Number Title Start Funding scheme
119905 Osteoclastogenesis and chronic inflammatory rheumatic disorders 01.12.2008 Project funding (Div. I-III)
119905 Osteoclastogenesis and chronic inflammatory rheumatic disorders 01.12.2008 Project funding (Div. I-III)

Abstract

1.Summary of the Research PlanBackground: Anti-TNF? treatment was shown to reduce the frequency of osteoclast precursor cells (OPCs) and tos top structural joint damage in rheumatoid arthritis (RA) and in spondarthritis patients as well. Blocking of TNF? with infliximab (chimeric monoclonal antibody to human TNF?) resulted in a strong reduction of bone resorption by OPCs in both diseases but did occur faster and more markedly in RA compared to patients with ankylosing spondylitis. This inhibition coincided with reduction of clinical disease activity in both patients cohorts and with an increase of serum osteocalcin levels and a relative decrease of collagen crosslinks in RA compared to AS patients. The initial marked inhibition of bone resorption by OPCs that were differentiated in vitro under the influence of M-CSF and RANKL was associated with apoptosis induction of OPCs and a concomitant decline of CD11b+/CD163+ circulating monocyte subpopulation that in contrast to CD11b+/CD16+ monocytes (inflammatory TNF? producing) can be differentiated into active osteoclasts. Besides apoptosis induction also downregulation of mobilization from bone marrow and of trafficking of OPCs into inflammatory sites and reduced differentiation of OPCs into bone resorbing osteoclasts at inflammatory sites could occur. Hypothesis: Inflammation induced osteoclastogenesis is largely dependent on TNF?. The rapid and sustained downregulation of osteoclastogenesis by TNF? inhibition (infliximab) is not only mediated by apoptosis of OPCs but also by reduced monocyte/OPC mobilization from bone marrow into peripheral tissues and by reduced attachment of OCPs to peripheral bone tissue and subsequently reduced differentiation into mature osteoclasts. Experimental design: hTNF?-transgenic mice that develop spontaneous arthritis will be crossed or not crossed with CX3CR1-EGFP knock-in (heterozygous) mice that exhibit endogenously labeled OPCs. Their offsprings will be investigated for the frequency of OPCs in bone marrow, circulation, spleen and inflamed joints by FACS and by immunohisto-chemistry respectively. Furthermore, the kinetics of trafficking of these cells into peripheral tissues in preclinical states and in distinct states of clinically established spontaneous arthritis with and without anti-TNF? (infliximab) treatment will be determined both by conventional intravital imaging (IVM) and by two photon IVM. Finally, changes in osteoclast number and density will be assessed by quantitative histomorphometrical analysis, and consequential changes in bone structure and mass will be visualized by MicroCT analysis of calvaria bone. Significance of the project: The proposed research combines expertise of clinical and basic research in chronic inflammatory diseases characterized by TNF?-driven synovial inflammation, osteoclastogenesis and joint destruction. The focus of this project lies on the elucidation of TNF?-mediated kinetics of mobilization and migration of osteoclast precursor cells (OPCs) from bone marrow into peripheral tissues in a mouse model of chronic arthritis. To this purpose, newly developed imaging techniques of intravital microscopy will be applied for the first time in a hTNF-transgenic x CX3CR1-EGFP knock-in arthritic mouse model to follow the fate of OPCs in a living mammal that suffers from chronic inflammation and the effects of anti-TNF treatment on this process will be tightly monitored. Thereby, we expect to elucidate the mechanisms by which therapeutic neutralization of TNF? can inhibit cytokine - mediated osteoclastogenesis in chronic inflammatory arthritis.
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