Cholecystokinin-antagonist lorglumide inhibits osteogenic differentiation in human bone marrow stem cells

Background: The relationship between gastrointestinal hormones and bone metabolism has gained significant attention, but the specific role of cholecystokinin (CCK) in bone homeostasis remains largely unexplored. This study aimed to evaluate the role of the CCK pathway in osteogenic differentiation by blocking its mechanisms in human bone marrow stem cells (hBMSCs). Methods: hBMSCs were exposed to Lorglumide, a CCK signaling pathway inhibitor, under osteogenic conditions. Cell viability, osteogenic differentiation, RT-qPCR analysis of CCK, FOS, OCN, and RUNX2, IP3 receptor phosphorylation, alkaline phosphatase (ALP) activity, and calcium concentration (Ca²) were assessed to elucidate Lorglumide's effects on osteogenesis and related mechanisms. Results: Lorglumide reduced hBMSC viability at concentrations ≥30 μM over 14 days. Mineralization assays revealed dose-dependent inhibition, with 20 μM maintaining mineralization comparable to controls. RT-qPCR showed that Lorglumide suppressed CCK expression and altered osteogenic gene expression (FOS, RUNX2, OCN). Lorglumide decreased Ca² concentration compared to osteogenic medium (OM) and reduced ALP activity, indicating its inhibitory effect on key osteogenic mechanisms. Conclusion: Lorglumide inhibits hBMSC osteoblastic differentiation, suggesting a possible role for the CCK signaling pathway in bone metabolism. These findings emphasize the involvement of gastrointestinal hormones in bone homeostasis, suggesting new therapeutic opportunities targeting hormonal regulation to promote bone health. Further studies are needed to explore the underlying mechanisms and potential clinical applications of modulating CCK pathways in bone-related disorders.