Salt-Induced Kinase Inhibitor Favors Osteoblast Differentiation During Mandibular Regeneration

Glucose metabolism plays a pivotal role in regulating a wide array of cellular physiological activities, encompassing osteogenic differentiation. Despite this, the potential benefits of targeting energy metabolism for enhancing bone regeneration remain largely unexplored. In this study, we delved into the impact and underlying mechanisms of the salt-induced kinase 2/3 (SIK 2/3) inhibitor, YKL-05-099 (YKL), on mandibular bone defects. We generated mandibular defect models with YKL local application and analyzed the new bone formation. Orofacial bone-marrow-derived mesenchymal stem cells (OMSCs) were cultured to evaluate the function and mechanism of YKL in osteogenic differentiation. YKL successfully enhanced new bone formation within the mandibular defect area without causing any organ damage. Furthermore, it promoted osteogenic differentiation of OMSCs by inhibiting SIK 2/3, which was accompanied by an increase in glucose uptake and ATP production. Mechanistically, glucose transporter 4 (Glut4) acted as a modulator of osteogenic differentiation by limiting AMPK pathway and preventing RUNX2 ubiquitinated degradation, and SIK 2/3 suppresses Glut4’s expression through the HDAC4/PGC-1α pathway. Collectively, our findings demonstrated YKL can promote osteogenic ability of OMSCs through Glut4-dependent glucose uptake, and SIK 2/3 negatively regulated level of Glut4 via HDAC4/PGC-1α pathway. These insights not only uncover a novel mechanism but also provide a solid foundation for the application of YKL in the context of mandibular bone defects.