EP2 Modulates Satellite Glial Cell Activation in Temporomandibular Joint Osteoarthritis Chronic Pain via p-ERK1/2 Signaling

Abstract

The etiology of chronic pain in temporomandibular joint osteoarthritis (TMJOA) is still unclear, making its treatment challenging in clinical practice. Emerging evidence suggests that the activation of satellite glial cells (SGCs) exerts an important role in the development of pain. This study aims to investigate whether and which prostaglandin E receptor (EP) subtypes expressed on peripheral SGCs and how the corresponding EP subtypes modulate SGC activation during TMJOA chronic pain. Immunofluorescence double staining was applied to demonstrate that EP2 and EP3 expressed on the activated SGCs in the trigeminal ganglions of mice. In vitro studies on the cultivation of primary SGCs showed that EP2 antagonist PF-04418948 significantly attenuated SGC activation in a dose-dependent manner, while EP3 agonist sulprostone failed to affect SGC activation. Kyoto Encyclopedia of Genes and Genomes analysis of RNA sequencing and Western blot demonstrated that the EP2-mediated signaling pathways were associated with phosphorylated extracellular signal–regulated kinase 1 and 2 (p-ERK1/2) signaling of mitogen-activated protein kinases (MAPKs). In addition, to verify the involvement of EP2 on SGCs in the activation of SGCs in vivo, a recombinant adeno-associated virus vector containing glial fibrillary acidic protein–shRNA (EP2)–enhanced green fluorescent protein was injected into TMJOA mouse ganglion of the third branch of the trigeminal nerve to knockdown EP2 on the SGCs. Taken together, EP2 modulates SGC activation through MAPK/p-ERK1/2 signaling in the chronic pain of monosodium iodoacetate–induced TMJOA. This study reveals a new mechanism of SGC activation, providing new insights for the treatment of chronic pain in TMJOA.