Selective glucocorticoid receptor modulator compound A, in contrast to prednisolone, does not induce leptin or the leptin receptor in human osteoarthritis synovial fibroblasts.
OBJECTIVE
Glucocorticoids are powerful anti-inflammatory compounds that also induce the expression of leptin and leptin receptor (Ob-R) in synovial fibroblasts through TGF-βsignalling and Smad1/5 phosphorylation. Compound A (CpdA), a selective glucocorticoid receptor agonist, reduces inflammation in murine arthritis models and does not induce diabetes or osteoporosis, thus offering an improved risk:benefit ratio in comparison with glucocorticoids. Due to the detrimental role of leptin in OA pathogenesis, we sought to determine whether CpdA also induced leptin and Ob-R protein expression as observed with prednisolone.


METHODS
Human synovial fibroblasts and chondrocytes were isolated from the synovium and cartilage of OA patients after joint surgery. The cells were treated with prednisolone, TGF-β1, TNF-α and/or CpdA. Levels of leptin, IL-6, IL-8, MMP-1 and MMP-3 were measured by ELISA and expression levels of Ob-R phospho-Smad1/5, phospho-Smad2, α-tubulin and glyceraldehyde 3-phosphate dehydrogenase were analysed by western blotting.


RESULTS
CpdA, unlike prednisolone, did not induce leptin secretion or Ob-R protein expression in OA synovial fibroblasts. Moreover, CpdA decreased endogenous Ob-R expression and down-regulated prednisolone-induced leptin secretion and Ob-R expression. Mechanistically, CpdA, unlike prednisolone, did not induce Smad1/5 phosphorylation. CpdA, similarly to prednisolone, down-regulated endogenous and TNF-α-induced IL-6, IL-8, MMP-1 and MMP-3 protein secretion. The dissociative effect of CpdA was confirmed using chondrocytes with no induction of leptin secretion, but with a significant decrease in IL-6, IL-8, MMP-1 and MMP-3 protein secretion.


CONCLUSIONS
CpdA, unlike prednisolone, did not induce leptin or Ob-R in human OA synovial fibroblasts, thereby demonstrating an improved risk:benefit ratio.
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Olivier
O
Malaise
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Biserka
B
Relic
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Florence
F
Quesada-Calvo
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Edith
E
Charlier
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Mustapha
M
Zeddou
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Sophie
S
Neuville
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Philippe
P
Gillet
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Edouard
E
Louis
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium.
Dominique
D
de Seny
Laboratory of Rheumatology and Laboratory of Gastroenterology, GIGA Research, CHU, University of Liège and Department of Orthopedic Surgery, CHU of Liège, CHU, Sart- Tilman B35, Liège, Belgium michel.malaise@ulg.ac.be.
Michel G
MG
Malaise
D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism*; D011239:Prednisolone / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D054411:Receptors, Leptin / Q000187:drug effects / Q000378:metabolism; D051896:Smad Proteins, Receptor-Regulated / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D015850:Interleukin-6; D016209:Interleukin-8; D020738:Leptin; D011965:Receptors, Glucocorticoid; D054411:Receptors, Leptin; D051896:Smad Proteins, Receptor-Regulated; D053773:Transforming Growth Factor beta1; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha; D011239:Prednisolone; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1
compound A; glucocorticoids; leptin; osteoarthritis; synovial fibroblast