Manzamine-A is a marine-derived alkaloid that has demonstrated antimalarial and antiproliferative properties and is an emerging drug lead compound as a possible intervention in certain cancers. This compound has been found to modulate SIX1 gene expression, a target that is critical for the proliferation and survival of cells via various developmental pathways. As yet, little research has focused on manzamine-A and how its use may affect tissue systems including bone. Here we hypothesized that manzamine-A, through its interaction with SIX1, would alter precursor cells that give rise to the bone cell responsible for remodeling: the osteoclast. We further hypothesized reduced effects in differentiated osteoclasts, as these cells are generally not mitotic. We interrogated the effects of manzamine-A on preosteoclasts and osteoclasts. qrtPCR, MTS cell viability, Caspase 3/7, and TRAP staining were used as a functional assay. Preosteoclasts show responsiveness to manzamine-A treatment exhibited by decreases in cell viability and an increase in apoptosis. Osteoclasts also proved to be affected by manzamine-A but only at higher concentrations where apoptosis was increased and activation was reduced. In summary, our presented results suggest manzamine-A may have significant effects on bone development and health through multiple cell targets, previously shown in the osteoblast cell lineage, the cell responsible for mineralized tissue formation, and here in the osteoclast, the cell responsible for the removal of mineralized tissue and renewal via precipitation of bone remodeling.

中文翻译：

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Manzamine-A 改变体外颅骨破骨细胞功能

Manzamine-A 是一种海洋生物碱，已证明具有抗疟疾和抗增殖特性，是一种新兴的药物先导化合物，可能干预某些癌症。人们发现这种化合物可以调节SIX1基因表达，这是通过各种发育途径对细胞增殖和存活至关重要的靶标。迄今为止，很少有研究关注曼扎明-A 及其使用如何影响包括骨骼在内的组织系统。在这里，我们假设曼扎明-A 通过与SIX1相互作用，会改变前体细胞，从而产生负责重塑的骨细胞：破骨细胞。我们进一步假设分化的破骨细胞的影响降低，因为这些细胞通常不进行有丝分裂。我们研究了曼扎明-A 对前破骨细胞和破骨细胞的影响。 qrtPCR、MTS 细胞活力、Caspase 3/7 和 TRAP 染色用作功能测定。前破骨细胞对曼扎明-A 治疗有反应，表现为细胞活力降低和细胞凋亡增加。破骨细胞也被证明受到曼扎明-A 的影响，但仅在浓度较高时，细胞凋亡增加，活化减少。总之，我们提出的结果表明，曼扎明-A 可能通过多个细胞靶标对骨骼发育和健康产生显着影响，先前在成骨细胞谱系（负责矿化组织形成的细胞）中显示，而在破骨细胞中（负责矿化组织形成的细胞）矿化组织的去除和通过骨重建沉淀的更新。