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