Expression of glutaminase Promotes Macrophage Recruitment in Periapical Leisions

Objectives: Recently, we have found out that tissue hypoxia stimulates the progression of periapical lesions by regulating apoptosis of osteoblasts. Other aspect of hypoxia-induced metabolic reprogramming in disease pathogenesis require further investigation. In this study, we examined the relationship between glutamine catabolism which is augmented by hypoxia in osteoblasts and the development of periapical lesions
Methods: Human osteoblasts were cultured under hypoxia. Expression of glutaminase 1 (GLS1) was examined by Western blot. Production of glutamate was measured by colorimetric assay. Knockdown of GLS1 was performed with siRNA technology. CCL2 secretion and chemotaxis of J774 macrophages were examined by enzyme-linked immunosorbent assay and Transwell migration assay, respectively. In a rat model of induced periapical lesions, the relations between disease progression and osteoblastic expression of GLS1/macrophage recruitment were studied.
Results: Hypoxia enhanced GLS1 expression and subsequent glutamate production in osteoblasts. Glutamate induced chemoattraction of macrophages by osteoblasts through upregulation of CCL2 synthesis. Hypoxia promoted CCL2 secretion and macrophage recruitment through augmentation of glutaminolysis. Knockdown of GLS1 abolished hypoxia-induced effects. In rat periapical lesions, progressive bone resorption significantly related to elevated GLS1 expression in osteoblasts and increased macrophage recruitment.
Conclusions: In addition to the rise in glycolytic activity, enhanced glutamine catabolism in osteoblasts is also related to the progression of periapical lesions. GLS1 may be a potential therapeutic target in the management of periapical lesions.