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THU0036 PPAR gamma agonist rosiglitazone could inhibit RA-FLS induced osteoclastogenesis by down-regulating RANKL expression and suppression of ERK phosphorylation
  1. X.N. Wei,
  2. L. Dai,
  3. L.J. Zhu,
  4. Y.Q. Mo,
  5. D.H. Zheng,
  6. B.Y. Zhang
  1. Division of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China


Background Experiments and clinical trial have shown that peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist could inhibit inflammation in rheumatoid arthritis (RA)[1,2]. Recent reports also showed that PPAR-γ agonist could prevent inflammatory periodontal bone loss by inhibiting receptor activator of NF-κB ligand (RANKL)-mediated osteoclastogenesis[3]. However, whether PPAR-γ agonist can inhibit bone erosion by RANKL-mediated osteoclastogenesis in RA is not clearly understood.

Objectives To investigate the effects and underlying mechanism of rosiglitazone (RSG), a high-affinity synthetic agonist for PPAR-γ, on rheumatoid synovial fibroblasts (RA-FLS) induced osteoclastogenesis.

Methods RA-FLS were cocultured with peripheral blood monocytes from healthy volunteers in the presence of macrophage colony-stimulating factor (M-CSF) and rosiglitazone (0, 15μM) for 14d. Osteoclast formation was assayed by tartrate-resistant acid phosphatase (TRAP) staining, and the RANKL/OPG mRNA was detected by Real-time PCR, the protein expression of RANKL, OPG, p-ERK, p-p38 and p-JNK was measured by Western blot. RA-FLS were cocultured with normal monocytes on bone slices for 14d, and rosiglitazone (0, 15μM) was then added from day 15, resorption lacunae area was identified by toluidine blue staining at day 21 and quantitated by Image Analysis Software.

Results 15μM rosiglitazone could significantly decrease the number of osteoclasts [(38±6) vs (85±10) per well,P<0.001] and the resorption lacunae area compared with control group without rosiglitazone [(12.64±1.96)% vs (25.97±8.60)%, P<0.05]. RANKL mRNA and protein expression from coculture system were significantly down-regulated by 15μM rosiglitazone, while OPG mRNA and protein were up-regulated, with RANKL/OPG mRNA and protein ratio down-regulated (all P<0.001). 15μM rosiglitazone significantly inhibited the expression of p-ERK protein (P<0.05), but not the expression of p-p38 or p-JNK protein (both P>0.05).

Conclusions Our results showed that PPAR-γ agonist rosiglitazone could inhibit RA-FLS induced osteoclastogenesis and bone resorption activity by down-regulating RANKL expression and suppression of ERK phosphorylation.

Funding This work is supported by Chinese National Natural Science Research Grant (no. 30572290 and 81001334), Guangdong Natural Science Research Grant (no. 9151008901000130 and 10451008901004542).

  1. Cuzzocrea S, Mazzon E, Dugo L, et al. Reduction in the evolution of murine type II collagen-induced arthritis by treatment with rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma. Arthritis Rheum, 2003, 48 (12): 3544-3556.

  2. Dina Shahin, Ehab El Toraby, Hala Abdel-Malek, et al. Effect of Peroxisome Proliferator-Activated Receptor Gamma Agonist (Pioglitazone) and Methotrexate on Disease Activity in Rheumatoid Arthritis (Experimental and Clinical Study). Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders, 2011, 4: 1-10.

  3. Hassumi MY, Silva-Filho VJ, Campos-Júnior JC, et al. PPAR-gamma agonist rosiglitazone prevents inflammatory periodontal bone loss by inhibiting osteoclastogenesis. Int Immunopharmacol, 2009, 9 (10): 1150-1158.

Disclosure of Interest None Declared

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