Inhibition of MAGL ameliorates glucocorticoid-induced bone loss by regulating the Nrf2 signaling

Glucocorticoids (GCs) are widely used for the treatment of autoimmune and inflammatory diseases. Unfortunately, the use of GCs is frequently accompanied by significant bone loss. Glucocorticoid-induced osteoporosis (GIO) represents a major adverse effect of glucocorticoid therapy. Increased osteoclastogenesis is a major contributor to bone loss, as osteoclasts are the primary cells responsible for bone resorption. However, the specific mechanisms by which GCs regulate osteoclast differentiation are still unclear. Monoacylglycerol lipase (MAGL) is a member of the α/β hydrolase superfamily, which can specifically hydrolyze endocannabinoid 2-arachidonoylglycerol (2-AG). As an important molecule within the endocannabinoid system, MAGL plays a regulatory role in the process of oxidative stress in multiple organs. It has been demonstrated that oxidative stress is associated with osteoclast differentiation. We hypothesized that MAGL might be involved in glucocorticoid-mediated regulation of osteoclast differentiation. Our experimental results demonstrated that GC treatment promoted osteoclast differentiation and led to a significant upregulation of MAGL. The knockdown of MAGL significantly suppressed the GC-induced enhancement of osteoclastogenesis and bone resorption. A series of in vitro experiments revealed that MAGL inhibition activated Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway, thereby significantly reducing oxidative stress levels. The modulation of GC-induced osteoclast differentiation by MAGL was mediated through the Keap1/Nrf2 signaling pathway. The results of in vivo experiments further demonstrated that MAGL inhibition effectively attenuated GC-induced bone loss. Thus, our study suggests that MAGL could represent a novel therapeutic target for GIO.