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Studying the therapeutic benefit of a glucocorticoid receptor phytomodulator in synoviocytes derived from rheumatoid arthritis patients

Valerie Gossye UGent (2009)
abstract
Rheumatoid arthritis (RA) is a chronic inflammatory ailment that is characterized by the hyperproliferative and invasive nature of fibroblast-like synoviocytes (FLS). Although research is advancing and therapies have greatly improved over the past years, current treatment regimens still suffer major drawbacks. This is unfortunately also the case for glucocorticoids (GCs), the most important and frequently used class of inflammatory drugs. Indeed, the usage of glucocorticoids (GCs) is overshadowed not only by the occurrence of severe side effects, such as osteoporosis, but also by the occurrence of resistance to the therapeutic effects of GCs, thereby limiting the treatment options of patients with RA. The main goal of GC/glucocorticoid receptor (GR) research thus remains to find new GR modulators that provide the same anti-inflammatory power, yet with reduced toxicity. A milestone in the history of identifying new, improved glucocorticoid receptor (GR) ligands, coincided with the recognition that activation (metabolic/unwanted effects) and repression (anti-inflammatory effects) of gene expression by GR could be addressed separately. Consequently, the objectives of this thesis were to unravel the therapeutic potential of Compound A (CpdA), a dissociative GR modulator, for the treatment of RA. In addition, it was questioned whether the anti-inflammatory effect of CpdA is associated with an improved side effect profile in comparison with currently available synthetic GCs, using the strong GR agonist dexamethasone (DEX) as a paradigm. In this work, the possible advantage of CpdA over DEX with regard to glucocorticoid-induced osteoporosis (GIO) and acquired resistance to the therapeutic effects of GCs was brought into special focus. As it is well known that cell lines and primary cells differ in their response to pro-inflammatory cytokines, a particularly important aspect of this research was the use of fibroblasts, isolated from the inflamed synovium of RA-patients, as a physiologically relevant ex vivo cell system to be able to unravel the molecular mechanisms by which CpdA exerts its effects.
Please use this url to cite or link to this publication:
author
promoter
UGent
organization
year
type
dissertation (monograph)
subject
keyword
Synovial fibroblast, Compound A, Rheumatoid Arthritis, glucocorticoids
pages
179 pages
place of publication
Gent
defense location
Het Pand
defense date
2009-03-11 16:00
language
English
UGent publication?
yes
classification
D1
copyright statement
I don't know the status of the copyright for this publication
id
526259
handle
http://hdl.handle.net/1854/LU-526259
alternative location
http://lib.ugent.be/fulltxt/RUG01/001/324/782/RUG01-001324782_2010_0001_AC.pdf
date created
2009-03-19 14:38:50
date last changed
2009-04-03 11:14:01
@phdthesis{526259,
  abstract     = {Rheumatoid arthritis (RA) is a chronic inflammatory ailment that is characterized by the hyperproliferative and invasive nature of fibroblast-like synoviocytes (FLS). Although research is advancing and therapies have greatly improved over the past years, current treatment regimens still suffer major drawbacks. This is unfortunately also the case for glucocorticoids (GCs), the most important and frequently used class of inflammatory drugs. Indeed, the usage of glucocorticoids (GCs) is overshadowed not only by the occurrence of severe side effects, such as osteoporosis, but also by the occurrence of resistance to the therapeutic effects of GCs, thereby limiting the treatment options of patients with RA. The main goal of GC/glucocorticoid receptor (GR) research thus remains to find new GR modulators that provide the same anti-inflammatory power, yet with reduced toxicity.
A milestone in the history of identifying new, improved glucocorticoid receptor (GR) ligands, coincided with the recognition that activation (metabolic/unwanted effects) and repression (anti-inflammatory effects) of gene expression by GR could be addressed separately. Consequently, the objectives of this thesis were to unravel the therapeutic potential of Compound A (CpdA), a dissociative GR modulator, for the treatment of RA. In addition, it was questioned whether the anti-inflammatory effect of CpdA is associated with an improved side effect profile in comparison with currently available synthetic GCs, using the strong GR agonist dexamethasone (DEX) as a paradigm. In this work, the possible advantage of CpdA over DEX with regard to glucocorticoid-induced osteoporosis (GIO) and acquired resistance to the therapeutic effects of GCs was brought into special focus. As it is well known that cell lines and primary cells differ in their response to pro-inflammatory cytokines, a particularly important aspect of this research was the use of fibroblasts, isolated from the inflamed synovium of RA-patients, as a physiologically relevant ex vivo cell system to be able to unravel the molecular mechanisms by which CpdA exerts its effects.},
  author       = {Gossye, Valerie},
  keyword      = {Synovial fibroblast,Compound A,Rheumatoid Arthritis,glucocorticoids},
  language     = {eng},
  pages        = {179},
  school       = {Ghent University},
  title        = {Studying the therapeutic benefit of a glucocorticoid receptor phytomodulator in synoviocytes derived from rheumatoid arthritis patients},
  url          = {http://lib.ugent.be/fulltxt/RUG01/001/324/782/RUG01-001324782\_2010\_0001\_AC.pdf},
  year         = {2009},
}

Chicago
Gossye, Valerie. 2009. “Studying the Therapeutic Benefit of a Glucocorticoid Receptor Phytomodulator in Synoviocytes Derived from Rheumatoid Arthritis Patients”. Gent.
APA
Gossye, V. (2009). Studying the therapeutic benefit of a glucocorticoid receptor phytomodulator in synoviocytes derived from rheumatoid arthritis patients. Gent.
Vancouver
1.
Gossye V. Studying the therapeutic benefit of a glucocorticoid receptor phytomodulator in synoviocytes derived from rheumatoid arthritis patients. [Gent]; 2009.
MLA
Gossye, Valerie. “Studying the Therapeutic Benefit of a Glucocorticoid Receptor Phytomodulator in Synoviocytes Derived from Rheumatoid Arthritis Patients.” 2009 : n. pag. Print.