PDF(Pubmed)
Abstract：
Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that during osteogenic differentiation, mRNA levels of most polyamine-associated enzymes are relatively constant, except for the catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), which is strongly increased at both mRNA and protein levels. As a result, the intracellular spermidine to spermine ratio is significantly reduced during the early stages of osteoblastogenesis. Supplementation of cells with exogenous spermidine or spermine decreases matrix mineralization in a dose-dependent manner. Employing N-cyclohexyl-1,3-propanediamine (CDAP) to chemically inhibit spermine synthase (SMS), the enzyme catalyzing conversion of spermidine into spermine, also suppresses mineralization. Intriguingly, this reduced mineralization is rescued with DFMO, an inhibitor of the upstream polyamine enzyme ornithine decarboxylase (ODC1). Similarly, high concentrations of CDAP cause cytoplasmic vacuolization and alter mitochondrial function, which are also reversible with the addition of DFMO. Altogether, these studies suggest that excess polyamines, especially spermidine, negatively affect hydroxyapatite synthesis of primary MSCs, whereas inhibition of polyamine synthesis with DFMO rescues most, but not all of these defects. These findings are relevant for patients with Snyder-Robinson syndrome (SRS), as the presenting skeletal defects-associated with SMS deficiency-could potentially be ameliorated by treatment with DFMO.
摘要：
尽管众所周知多胺与许多生命形式相关，人们对多胺如何调节成骨和骨骼稳态知之甚少。这里,我们报道了一系列使用人骨髓来源的多能基质细胞(MSCs)进行的体外研究.首先,我们表明在成骨分化过程中，大多数多胺相关酶的mRNA水平相对恒定，除了分解代谢酶亚精胺/精胺N1-乙酰转移酶1（SAT1），在mRNA和蛋白质水平上都强烈增加。因此,在成骨细胞形成的早期阶段，细胞内亚精胺与精胺的比例显着降低。用外源亚精胺或精胺补充细胞以剂量依赖性方式减少基质矿化。使用N-环己基-1,3-丙二胺（CDAP）化学抑制精胺合成酶（SMS），催化亚精胺转化为精胺的酶，也抑制了矿化。有趣的是，这种减少的矿化被DFMO拯救，上游多胺酶鸟氨酸脱羧酶（ODC1）的抑制剂。同样，高浓度的CDAP导致细胞质空泡化并改变线粒体功能，加入DFMO也是可逆的。总之,这些研究表明，过量的多胺，尤其是亚精胺,对原代MSCs的羟基磷灰石合成产生负面影响，而用DFMO抑制多胺合成拯救最多，但不是所有这些缺陷。这些发现与Snyder-Robinson综合征（SRS）患者有关，因为存在的与SMS缺乏相关的骨骼缺陷可能通过DFMO治疗得到改善。
