Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling.
Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling.
复制标题
DOI：
10.1016/j.bbrc.2011.05.001
复制
发表时间：
2011-06
影响因子：
3.1
通讯作者：
T. Yonezawa;Ji-Won Lee;Ayaka Hibino;Midori Asai;H. Hojo;Byung‐Yoon Cha;T. Teruya;K. Nagai;U. Chu
中科院分区：
文献类型：
--
作者：
T. Yonezawa;Ji-Won Lee;Ayaka Hibino;Midori Asai;H. Hojo;Byung‐Yoon Cha;T. Teruya;K. Nagai;U. Chu
骨量受成骨细胞介导的骨形成和破骨细胞介导的骨吸收调节。我们之前报道了一种β-碳碱生物碱——毒芹碱，在体外和体内抑制破骨细胞分化和骨吸收。在本研究中，我们研究了鼠尾草碱对成骨细胞增殖、分化和矿化的影响。鼠碱促进MC3T3-E1细胞碱性磷酸酶（ALP）活性，但不影响其增殖。hammine还增加了成骨细胞标记基因aland骨钙素的mRNA表达。此外，伤害碱能增强MC3T3-E1细胞的矿化。鼠碱还能诱导初代颅骨成骨细胞和间充质干细胞C3H10T1/2细胞的成骨细胞分化。利用与毒胺相关的β-碳碱生物碱进行构效关系研究发现，毒胺的C3-C4双键和7-羟基或7-甲氧基对其成骨活性起重要作用。骨形态发生蛋白（BMP）拮抗剂noggin及其受体激酶抑制剂dorsomorphin和LDN-193189减弱了伤害素促进的ALP活性。此外，害人碱增加了bmp -2、Bmp-4、Bmp-6、bmp -7及其靶基因id1的mRNA表达。hammine还增强了runx2和dosterix mRNA的表达，这是成骨细胞分化的关键转录因子。此外，bmp反应性和runx2反应性报告基因通过伤害处理被激活。综上所述，这些结果表明，伤害碱可能通过诱导BMP的表达和激活BMP和Runx2通路来增强成骨细胞的分化。我们的研究结果表明，鼠尾草碱具有骨合成代谢作用，可能作为一种先导化合物用于治疗骨质减少疾病和骨再生。
Bone mass is regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. We previously reported that harmine, a β-carboline alkaloid, inhibits osteoclast differentiation and bone resorptionin vitroandin vivo. In this study, we investigated the effects of harmine on osteoblast proliferation, differentiation and mineralization. Harmine promoted alkaline phosphatase (ALP) activity in MC3T3-E1 cells without affecting their proliferation. Harmine also increased the mRNA expressions of the osteoblast marker genesALPandOsteocalcin. Furthermore, the mineralization of MC3T3-E1 cells was enhanced by treatment with harmine. Harmine also induced osteoblast differentiation in primary calvarial osteoblasts and mesenchymal stem cell line C3H10T1/2 cells. Structure–activity relationship studies using harmine-related β-carboline alkaloids revealed that the C3–C4 double bond and 7-hydroxy or 7-methoxy group of harmine were important for its osteogenic activity. The bone morphogenetic protein (BMP) antagonist noggin and its receptor kinase inhibitors dorsomorphin and LDN-193189 attenuated harmine-promoted ALP activity. In addition, harmine increased the mRNA expressions ofBmp-2,Bmp-4,Bmp-6,Bmp-7and its target geneId1. Harmine also enhanced the mRNA expressions ofRunx2andOsterix, which are key transcription factors in osteoblast differentiation. Furthermore, BMP-responsive and Runx2-responsive reporters were activated by harmine treatment. Taken together, these results indicate that harmine enhances osteoblast differentiation probably by inducing the expressions of BMPs and activating BMP and Runx2 pathways. Our findings suggest that harmine has bone anabolic effects and may be useful for the treatment of bone-decreasing diseases and bone regeneration as a lead compound.