PPAR-δ agonist affects adipo-chondrogenic differentiation of human mesenchymal stem cells through the expression of PPAR-γ

INTRODUCTION: Peroxisome proliferator–activated receptor (PPAR) subfamily play an important role in chondrogenesis. Previous study has reported that mixture of GW0742 (PPAR-δ agonist), hyaluronic acid (HA) and mesenchymal stem cells (MSCs) enhance chondrogenesis. The purpose of this study is to compare with efficacies of commercially available HA and demonstrate correlation of PPAR-γ and PPAR-δ. METHODS: In this experimental study, MSCs were cultured with chondrogenic media and clinical HA gels (Euflexxa®, Synvisc®, Orthovisc® and Supartz®) using micormass culture method. Expression of type Ⅰ, Ⅱ collagen and matrix metalloprotease-13 (MMP-13) was measured by immunoblotting. MSCs were cultured with chondrogenic media and/or HA and/or GW0742 and/or rosiglitazone (PPAR-γ agonist) and/or human osteoarthritis synovial fluid. Immunoblotting was used to measure expression of type Ⅱ collagen and PPAR-γ. To identify the effective dose for chondrogenesis and adipogenesis, either 0.1, 1, 5 or 10 μM of rosiglitazone was added to MSCs in chondrogenic media or adipogenic media. RESULTS: Clinical HA gels inhibited expression of type Ⅰ collagen and enhanced the expression of MMP-13. Type Ⅱ collagen expression was significantly elevated in all treatment groups except Supartz®. GW0742 decreased the expression of PPAR-γ with/without inflammation condition. Rosiglitazone enhanced adipogenesis in a dose-dependent manner and enhanced the expression of type Ⅱ collagen under inflammation condition. Otherwise, the expression of type Ⅱ collagen and formation of chondrocyte spheroids showed a dose-dependent manner with a peak at 1 μM of rosiglitazone. CONCLUSIONS: PPAR-γ has a considerable anti-inflammatory effect and a strong pro-adipogenic effect, which inhibits the chondrogenic effect. PPAR-γ is related with PPAR-δ and shows a chondrogenic effect at lower concentrations. And clinical HA gels shows various efficacy of chondrogenesis. This study suggested that PPAR-γ and PPAR-δ are key regulatory factors of chondrogenesis.