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.