Irg1 regulates bone homeostasis via regulating the Grk5 expression

• Published in: Biochemical and biophysical research communications 2024-11, Vol.734, p.150786, Article 150786
• Main Authors: Sun, Xuewu, Zhang, Boya, Yuan, Putao, Ye, Huali, Shi, Peihua
• Format: Article
• Language: English
• Subjects: Animals; Bone and Bones - diagnostic imaging; Bone and Bones - metabolism; Carboxy-Lyases - genetics; Carboxy-Lyases - metabolism; Cell Differentiation; Cells, Cultured; G-Protein-Coupled Receptor Kinase 5 - genetics; G-Protein-Coupled Receptor Kinase 5 - metabolism; Homeostasis; Hydro-Lyases - genetics; Hydro-Lyases - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoclasts - cytology; Osteoclasts - metabolism; Osteogenesis - genetics; Signal Transduction; Succinates - metabolism
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150786

We have previously demonstrated that itaconic acid can regulate osteoclast differentiation in vitro and in vivo, thereby affecting the progression of osteoporosis. The role of Irg1 as itaconic acid catalytic enzyme in bone homeostasis has not been clearly elucidated. Here, we detected enhanced the osteoclast differentiation in Irg1-deficiency BMMs, along with the expression of genes associated with osteoclastogenesis. Irg1 knockout promoted the expression of Nfatc1 and F-actin ring formation, with the inhibited production of itaconate. RNA-seq analysis was carried out and we proved that Grk5 expression was increased the most. Inhibition of Grk5 attenuated the effect of Irg1 in the osteoclastogenesis. However, micro-CT analysis showed no significant difference of bone trabecular structure in Irg1 knockout mice. Moreover, we observed no significant difference of osteoclasts numbers in the femur of Irg1 knockout mice in vivo. And similar bone formation was detected between the Irg1 knockout and WT mice, indicating that irg1 had slight effect on the bone homeostasis under physiological conditions. Surprising, we detected higher level of inflammatory factors in the bone tissues of Irg1 knockout mice. Above all, we for the first time demonstrated that Irg1 knockout promoted the osteoclastogenesis via regulating the Grk5 signaling. Regulation of irg1-Grk5 axis could be effective in treating human diseases under pathological situations in the future. •Irg1 deficiency promoted the osteoclast differentiation in vitro.•Besides inducing itaconate, Irg1 regulates the osteoclast differentiation via regulating the Grk5 expression and activity.•Irg1 has no effect on the bone balance under physiological condition in vivo.•Irg1 inhibits the expression of inflammatory factors in vivo.