The role of SREBP-1c signaling pathway in osteoblast pyroptosis and the protective effect of D-pinitol

Preclinical animal studies and human trials have indicated that D-pinitol may have multiple beneficial properties, such as regulating lipid metabolism and anti-osteoporosis. The purpose of this research was to use in vivo and in vitro methods to explore lipid-induced pyroptosis in osteogenic differentiation and osteoporosis development, while also examining DP's regulatory role in preventing osteoblast pyroptosis. Results demonstrated that daily oral administration of D-pinitol (DP) at a clinically relevant dose significantly ameliorated bone microarchitecture deterioration in apolipoprotein A1-deficient (ApoA1 −/− ) mice. DP increased Runx2 and OST expressions, and enhanced the bone-mineralized nodules production in ox-LDL-treated MC3T3-E1 cells. DP also lowered pyroptosis-related indicators such as NLRP3, Caspase-1, GSDMD, GSDMD N-terminal (GSDMD-NT), Cleaved caspase-1, and IL-1β. Mechanistically, we found that DP inhibited NLRP3-mediated pyroptosis by downregulating SREBP-1c and altering p53 and Galectin-1 signaling. Our findings indicated that SREBP-1c is involved in lipid metabolism disorder-induced activation of the NLRP3 and ultimately results in osteogenic pyroptosis. DP could inhibit the SREBP-1c pathway to protect osteoblasts, thereby ameliorating osteoporosis. Diagrammatic illustration of the working model showing how the DP inhibits the SREBP-1c signaling pathway to reduce osteoblast pyroptosis caused by lipid dysmetabolism. • DP administration inhibits bone pyroptosis and rescued bone loss in ApoA1−/− mice. • Ox-LDL-induced lipid accumulation caused osteoblasts to undergo pyroptotic cell death via SREBP-1 activation. • Treatment with DP markedly attenuated ox-LDL mediated the inhibition of bone formation and osteogenic pyroptosis. • DP inhibited the SREBP-1c pathway via altering its downstream signaling pathways, such as p-p53 and Galectin-1 to protect osteoblasts from lipid metabolic dysfunction-induced pyroptosis thereby ameliorating osteoporosis.