ScopeThis paper aims to explore the osteogenic activity and potential mechanism of the peptideācalcium chelate, and provides a theoretical basis for peptideācalcium chelates as functional foods to prevent or improve osteoporosis.Methods and resultsIn this research, a novel peptide (PheāGlyāLeu, FGL) with a high calciumābinding capacity is screened from bovine bone collagen hydrolysates (CPs), calcium binding sites of which mainly included carbonyl, amino and carboxyl groups. The FGLāCa significantly enhances the osteogenic activity of MC3T3āE1 cells (survival rate, differentiation, and mineralization). The results of calcium fluorescence labeling and molecular docking show that FGLāCa may activate calciumāsensing receptor (CaSR), leading to an increase in intracellular calcium concentration, then enhancing osteogenic activity of MC3T3āE1 cells. Further research found that FGLāCa significantly promotes the mRNA and protein expression levels of CaSR, transforming growth factor Ī² (TGFāĪ²1), TGFāĪ²ātype II receptor (TĪ²RII), Smad2, Smad3, osteocalcin (OCN), alkaline phosphatase (ALP), osteoprotegrin (OPG), and collagen type I (COLI). Subsequently, in the signal pathway intervention experiment, the expression levels of genes and proteins related to the TGFāĪ²1/Smad2/3 signaling pathway that are promoted by FGLāCa are found to decrease.ConclusionsThese results suggest that FGLāCa may activate CaSR, increase intracellular calcium concentration, and activate TGFāĪ²1/Smad2/3 signaling pathway, which may be one of the potential mechanisms for enhancing osteogenic activity.