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

IF 2.2 3区生物学 Q4 CELL BIOLOGY

Differentiation Pub Date : 2025-05-01 DOI:10.1016/j.diff.2025.100867

Catharina Marques Sacramento, Márcio Zaffalon Casati, Enilson Antonio Sallum, Renato Corrêa Viana Casarin, Karina Gonzales Silvério

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Abstract

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.

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胆囊收缩素拮抗剂洛格鲁胺抑制人骨髓干细胞成骨分化

胃肠激素与骨代谢之间的关系已引起广泛关注，但胆囊收缩素（CCK）在骨稳态中的具体作用仍未得到充分研究。本研究旨在通过阻断CCK通路在人骨髓干细胞（hBMSCs）中的机制来评估CCK通路在成骨分化中的作用。方法在成骨条件下，将骨髓间充质干细胞暴露于CCK信号通路抑制剂洛格鲁胺中。通过细胞活力、成骨分化、CCK、FOS、OCN和RUNX2的RT-qPCR分析、IP3受体磷酸化、碱性磷酸酶（ALP）活性和钙浓度（Ca2）的测定来阐明洛格鲁米对成骨的影响及其相关机制。结果浓度≥30 μM的sloglumide在14天内降低hBMSC活力。矿化试验显示剂量依赖性抑制，20 μM维持矿化与对照组相当。RT-qPCR结果显示，洛格鲁胺抑制CCK表达，改变成骨基因（FOS、RUNX2、OCN）表达。与成骨培养基（OM）相比，洛格鲁胺降低Ca2浓度，降低ALP活性，表明其对关键的成骨机制有抑制作用。结论洛格鲁胺抑制hBMSC成骨细胞分化，提示CCK信号通路可能参与骨代谢。这些发现强调了胃肠激素在骨稳态中的作用，提示了针对激素调节促进骨健康的新治疗机会。需要进一步的研究来探索调节CCK通路在骨相关疾病中的潜在机制和潜在的临床应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Differentiation 生物-发育生物学

CiteScore

4.10

自引率

3.40%

发文量

审稿时长

51 days

期刊介绍： Differentiation is a multidisciplinary journal dealing with topics relating to cell differentiation, development, cellular structure and function, and cancer. Differentiation of eukaryotes at the molecular level and the use of transgenic and targeted mutagenesis approaches to problems of differentiation are of particular interest to the journal. The journal will publish full-length articles containing original work in any of these areas. We will also publish reviews and commentaries on topics of current interest. The principal subject areas the journal covers are: • embryonic patterning and organogenesis • human development and congenital malformation • mechanisms of cell lineage commitment • tissue homeostasis and oncogenic transformation • establishment of cellular polarity • stem cell differentiation • cell reprogramming mechanisms • stability of the differentiated state • cell and tissue interactions in vivo and in vitro • signal transduction pathways in development and differentiation • carcinogenesis and cancer • mechanisms involved in cell growth and division especially relating to cancer • differentiation in regeneration and ageing • therapeutic applications of differentiation processes.