Background/Purpose: Fibroblast-like synoviocytes (FLS) play important roles in rheumatoid arthritis (RA) by producing matrix metalloproteinase (MMP) and cytokines, and hence, these cells are a therapeutic target. Another unique characteristic of FLS is their ability to differentiate into mesenchymal multilineage cells, such as osteoblasts, chondrocytes, and adipocytes. Based on this characteristic, we proposed that the induction of adipogenesis in FLS would ameliorate RA activity by reducing cytokine and protease secretion from the cell. Thus, in this study, we treated FLS with plant-derived natural PPARγ ligands—arterpilin-C —to induce adipogenesis in FLS and evaluated the MMP secretion from FLS following adipogenesis induction.

Methods: The FLS derived from RA patients (Articular Engineering, USA) were maintained in Dulbecco’s Modification of Eagles Medium with 10% fetal bovine serum. To induce adipogenesis via FLS, we added arterpilin-C to the culture medium in the presence or absence of dexamethasone. Lipid deposition in FLS was examined by using Oil red O or LipidTOX™ (Molecular Probes, USA) staining. To confirm adipogenic differentiation, we used anti-fatty acid binding protein 4 antibodies for immunostaining. A quantitative polymerase chain reaction using SYBR Green was performed to determine the expression levels of the transcripts.

Results: Droplets were observed in the cytoplasm of FLS after a 3-week culture with arterpilin-C (30 µM) in the presence of dexamethasone. Oil red O or LipidTOX staining confirmed adipogenesis by FLS. The expression of FABP4, an adipocyte-specific protein, was also noted in the cells with droplets by immunostaining. However, adipogenesis by arterpilin-C was achieved only in the presence of dexamethasone in a dose-dependent manner. The minimum dexamethasone concentration required for adipogenesis induction by arterpilin-C in FLS was 10^-7 M. PPARγ protein expression was clearly enhanced in FLS treated with a dexamethasone concentration of 10^-7M. Moreover, the MMP1 and MMP2 mRNA expressions were lower in the FLS following adipogenesis induced by arterpilin-C, compared to the FLS treated only with dexamethasone.

Conclusion: These data suggest that the natural PPARγ ligands, arterpilin-C , can be used to induce adipogenesis in FLS. Importantly, the expressions of MMP1 and MMP2 were significantly reduced in FLS following adipogenesis induced by these natural PPARγ ligands. Since these proteinases are important in RA disease progression, induction of adipogenesis in FLS may contribute to inhibiting joint destruction in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/reduction-in-matrix-metalloproteinase-1-and-2-secretion-from-fibroblast-like-synoviocytes-after-induction-of-adipogenesis-by-a-natural-peroxisome-proliferator-activated-receptor-gamma-ligand-arterpi/