Article (Scientific journals)
15-Deoxy-Δ-12, 14-prostaglandin J2 acts cooperatively with prednisolone to reduce TGF-β-induced pro-fibrotic pathways in human osteoarthritis fibroblasts
Vaamonde-Garcia, Carlos; MALAISE, Olivier; CHARLIER, Edith et al.
2019In Biochemical Pharmacology
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Keywords :
Fibroblast-like-synoviocytes; Fibrosis; Glucocorticoids; Osteoarthritis; Peroxisome proliferator-activated receptor-γ agonist; Transforming growth factor-β1
Abstract :
[en] BACKGROUND/AIMS: Synovial fibrosis is a pathological process that is observed in several musculoskeletal disorders and characterized by the excessive deposition of extracellular matrix, as well as cell migration and proliferation. Despite the fact that glucocorticoids are widely employed in the treatment of rheumatic pathologies such as osteoarthritis (OA) and rheumatoid arthritis, the mechanisms by which glucocorticoids act in the joint and their impacts on pro-fibrotic pathways are still unclear. MATERIALS: Human OA synovial fibroblasts were obtained from knee and hip joints. Cells were treated with prednisolone (1 mM) or transforming growth factor-beta 1 (TGF-β1) (10 ng/ml) for 1 and 7 days for quantification of RNA and protein expression (by real-time quantitative reverse transcription-PCR and western blot, respectively), 72 h for immunocytochemistry analysis, and 48 h for proliferation (by BrdU assay) and migration (by wound assay) studies. In addition, cells were preincubated with prednisolone and/or the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) for 6 h before adding TGF-β1. pSmad1/5, pSmad2 and β-catenin levels were analyzed by Western blot. The activin receptor-like kinase-5 (ALK-5) inhibitor (SB-431542) was employed for the mechanistic assays. RESULTS: Prednisolone showed a predominant anti-fibrotic impact on fibroblast-like synoviocytes as it attenuated the spontaneous and TGF-β-induced gene expression of pro-fibrotic markers. Prednisolone also reduced α-sma protein and type III collagen levels, as well as cell proliferation and migration after TGF-β stimulation. However, prednisolone did not downregulate the gene expression of all the pro-fibrotic markers tested and did not restore the reduced PPAR-γ levels after TGF-β stimulation. Interestingly, anti-fibrotic actions of the glucocorticoid were reinforced in the presence of the PPAR-γ agonist 15d-PGJ2. Combined pretreatment modulated Smad2/3 levels and, similar to the ALK-5 inhibitor, blocked β-catenin accumulation elicited by TGF-β. CONCLUSIONS: Prednisolone, along with 15d-PGJ2, modulates pro-fibrotic pathways activated by TGF-β in synovial fibroblasts at least partially through the inhibition of ALK5/Smad2 signaling and subsequent β-catenin accumulation. These findings shed light on the potential therapeutic effects of glucocorticoids treatment combined with a PPAR-γ agonist against synovial fibrosis, although future studies are warranted to further evaluate this concern.
Disciplines :
Rheumatology
Author, co-author :
Vaamonde-Garcia, Carlos;  University of A Coruña > Department of Physiotherapy > Tissue Engineering and Cellular Therapy Group
MALAISE, Olivier ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de rhumatologie
CHARLIER, Edith ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de rhumatologie
DEROYER, Céline  ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de rhumatologie
NEUVILLE, Sophie ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de rhumatologie
GILLET, Philippe ;  Centre Hospitalier Universitaire de Liège - CHU > Département de chirurgie > Service de chirurgie de l'appareil locomoteur
Kurth, William  ;  Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
Meijide-Failde, Rosa;  University of A Coruña > Department of Physiotherapy > Tissue Engineering and Cellular Therapy Group
MALAISE, Michel ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de rhumatologie
DE SENY, Dominique ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de rhumatologie
Language :
English
Title :
15-Deoxy-Δ-12, 14-prostaglandin J2 acts cooperatively with prednisolone to reduce TGF-β-induced pro-fibrotic pathways in human osteoarthritis fibroblasts
Publication date :
July 2019
Journal title :
Biochemical Pharmacology
ISSN :
0006-2952
eISSN :
1873-2968
Publisher :
Elsevier, Netherlands
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 24 July 2019

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