Agonists of peroxisome proliferators-activated receptors (PPAR) α, β/δ or γ reduce transforming growth factor (TGF)-β-induced proteoglycans' production.

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Agonists of peroxisome proliferators-activated receptors (PPAR) α, β/δ or γ reduce transforming growth factor (TGF)-β-induced proteoglycans' production in chondrocytes P.E. Poleni, M.Sc., A. Bianchi, Ph.D., S. Etienne, M.Sc., M. Koufany, B.Sc., S. Sebillaud, B.Sc., P. Netter, M.D., Ph.D., B. Terlain, Pharm.D., J.Y. Jouzeau, Pharm.D., Ph.D. Osteoarthritis and Cartilage Volume 15, Issue 5, Pages 493-505 (May 2007) DOI: 10.1016/j.joca.2006.10.009 Copyright © 2006 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Selectivity of synthetic PPAR agonists for PPAR target genes in chondrocytes. Rat chondrocytes, embedded in alginate beads (5×104cells/bead) were exposed or not to Wy14643 (10–30μM, PPARα agonist), GW501516 (0.1–100nM, PPARβ/δ agonist) or ROSI (1–10 μM, PPARγ agonist) for 48h. Data expressed as mean levels of mRNA of specific target genes normalized to RP29 (n=4–8): (A) ACO for PPARα; (B) CPT-1 for PPARβ/δ; (C) adiponectin for PPARγ. Osteoarthritis and Cartilage 2007 15, 493-505DOI: (10.1016/j.joca.2006.10.009) Copyright © 2006 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Reversion of PPAR target genes' expression by selective antagonists in chondrocytes. Rat chondrocytes, embedded in alginate beads (5×104cells/bead), were exposed or not to Wy14643 (100μM), GW501516 (100nM), or ROSI (10μM), in the presence or absence of PPARα (GW6471, 10μM) or PPARγ (GW9662, 10μM) antagonists for 48h. Data are expressed as mean±s.e.m. of normalized mRNA levels for ACO, CPT-1 or adiponectin quantified by real time PCR (n=4). Statistically significant differences from the control are indicated as *, P<0.05; **, P<0.01, ***, P<0.001, and from “PPAR agonists”-treated cells as §, P<0.05; §§, P<0.01; §§§, P<0.001. Osteoarthritis and Cartilage 2007 15, 493-505DOI: (10.1016/j.joca.2006.10.009) Copyright © 2006 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Effects of selective PPAR agonists on TGF-β1-induced changes in PG metabolism in chondrocytes. Chondrocytes, embedded in alginate beads (5×104cells/bead), were exposed or not to Wy14643 (100μM), GW501516 (100nM) or ROSI (10μM) for 2h before stimulation with TGF-β1 (10ng/ml), alone or in combination with PPAR agonists, for 72h. (A) GAG content after solubilization of alginate beads (n=10); (B) representative sections of Alcian blue staining of beads (n=5); (C) PG synthesis by incorporation of radiolabelled sulphate (n=5). Data are expressed as mean±s.e.m. Statistically significant differences from the control are indicated as *, P<0.05; **, P<0.01; ***, P<0.001 and from TGF-β1-treated cells as #, P<0.05; ##, P<0.01; ###, P<0.001. Osteoarthritis and Cartilage 2007 15, 493-505DOI: (10.1016/j.joca.2006.10.009) Copyright © 2006 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Effects of selective PPAR agonists on TGF-β1-induced signalling pathways in chondrocytes. Rat chondrocytes, embedded in alginate beads (5×104cells/bead), were exposed or not to Wy14643 (100μM), GW501516 (100nM) or ROSI (10μM) for 2h before stimulation with TGF-β1 (10ng/ml), alone or in combination with PPAR agonists, for 1h. Phosphorylation of Smad, ERK1/2 and p38-MAPK were evaluated by Western Blot (n=3). (A) Time course effect of Smad2/3, ERK1/2 and p38-MAPK phosphorylation in response to TGF-β1; (B) effect of selective PPAR agonists on TGF-β1-induced phosphorylation of Smad2/3; (C) effect of selective PPAR agonists on TGF-β1-induced phosphorylation of ERK1/2. Data are expressed as mean±s.e.m. Statistically significant differences from the control are indicated as *P<0.05; **, P<0.01; ***, P<0.001 and from TGF-β1-treated cells as #, P<0.05; ##, P<0.01; ###, P<0.001. Osteoarthritis and Cartilage 2007 15, 493-505DOI: (10.1016/j.joca.2006.10.009) Copyright © 2006 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 Effects of selective PPAR agonists on TGF-β1-induced PGE2 production in chondrocytes. Rat chondrocytes, embedded in alginate beads (5×104cells/bead), were exposed or not to Wy14643 (100μM), GW501516 (100nM) or ROSI (10μM) for 2h before stimulation with TGF-β1 (10ng/ml), alone or in combination with PPAR agonists, for 24h. PGE2 level was measured by EIA assays in culture supernatants (n=4). Data are expressed as mean±s.e.m. Statistically significant differences from the control are indicated as *P<0.05; **, P<0.01; ***, P<0.001 and from TGF-β1-treated cells as #, P<0.05; ##, P<0.01; ###, P<0.001. Osteoarthritis and Cartilage 2007 15, 493-505DOI: (10.1016/j.joca.2006.10.009) Copyright © 2006 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 Reversion of anti-anabolic potency of PPAR agonists by selective antagonists in chondrocytes. Rat chondrocytes, embedded in alginate beads (5×104cells/bead), were exposed or not for 2h with Wy14643 (100μM), GW501516 (100nM), or ROSI (10μM), in the presence or absence of PPARα (GW6471, 10μM) or PPARγ (GW9662, 10μM) antagonists, before stimulation with 10ng/ml TGF-β1, alone or in combination with PPAR ligands, for 48h. Data are expressed as mean±s.e.m. of normalized mRNA levels quantified by real time PCR (n=4). (A) Aggrecan expression; (B) TGF-β1 expression. Statistically significant differences from the control are indicated as *, P<0.05; **, P<0.01, ***, P<0.001, from TGF-β1-treated cells as #, P<0.05; ##, P<0.01; ###, P<0.001 and from “TGF-β1+PPAR agonists”-treated cells as §, P<0.05; §§, P<0.01; §§§, P<0.001. Osteoarthritis and Cartilage 2007 15, 493-505DOI: (10.1016/j.joca.2006.10.009) Copyright © 2006 Osteoarthritis Research Society International Terms and Conditions