Morin Exerts Anti-Arthritic Effects by Attenuating Synovial Angiogenesis via Activation of Peroxisome Proliferator Activated Receptor-γ

Scope Methods and results Morin, a flavonoid occurring in many dietary plants, can reduce the number of synovial blood vessels and ameliorate collagen-induced arthritis (CIA) in rats. Herein, its underlying mechanisms in view of the peroxisome proliferator activated receptor-gamma (PPAR gamma) pathway are addressed. In vitro, wound-healing and transwell assays are conducted to explore the effect of morin on HUVECs migration. Morin inhibits HUVECs migration and tube formation induced by VEGF, which is reversed by PPAR gamma antagonist GW9662 or siPPAR gamma. Molecular docking and competitive binding assays show that morin could bind to PPAR gamma. Morin increases the expression of PDK4 and CD36 in a PPAR gamma-dependent manner and increases the luciferase activity in cells transfected with PPAR gamma plasmid, which indicates that morin could activate PPAR gamma after binding. In addition, morin increases the expression of PTEN, a target gene of PPAR gamma that suppresses angiogenesis and inhibits PI3K/Akt signaling. The effects of morin on the PTEN-PI3K/Akt pathway are diminished by GW9662 and siPPAR gamma. In vivo studies show that morin ameliorates rat CIA, reduces synovial angiogenesis, and upregulates the expression of PTEN in the synovium, which is almost completely abolished by GW9662. Conclusions Morin is a potential agonist of PPAR gamma, which attenuates synovial angiogenesis and arthritis via the PPAR gamma-PTEN-PI3K/Akt pathway.