Impact of the SIK3 pathway inhibition on osteoclast differentiation via oxidative phosphorylation.

This article investigates the role of salt-inducible kinase 3 (SIK3), a regulator of cellular energy metabolism, in osteoclast differentiation and bone resorption. Using osteoclast-specific SIK3 conditional knockout mice, the study found increased bone mass and an osteopetrosis phenotype, indicating impaired bone resorption due to reduced osteoclast activity. The SIK3 inhibitor pterosin B suppressed osteoclast differentiation and resorption in vitro by affecting mitochondrial function, particularly oxidative phosphorylation and the tricarboxylic acid cycle, thereby disrupting ATP production essential for osteoclast function. These findings highlight the LKB1-SIK3 signaling pathway as a key metabolic regulator in osteoclastogenesis and suggest that targeting SIK3 may offer a novel therapeutic approach for osteoporosis and related bone diseases.