A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-β-catenin signaling.
A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-β-catenin signaling.
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DOI：
10.1038/cddis.2014.350
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发表时间：
2014-09-18
影响因子：
9
通讯作者：
Trivedi R
中科院分区：
文献类型：
--
作者：
Kushwaha P;Khedgikar V;Gautam J;Dixit P;Chillara R;Verma A;Thakur R;Mishra DP;Singh D;Maurya R;Chattopadhyay N;Mishra PR;Trivedi R
最近，我们报道了黄檀树叶和豆荚提取物具有抗吸收和成骨作用。黄檀提取物中存在的活性分子所致的正骨骼效应。7-O-[β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside]是一种新的异黄酮类化合物，在提取物中所占比例较高。在这里，我们通过刺激骨形态发生蛋白2(BMP2)和Wnt/β-Catenin机制，展示了CAFG作为一种替代合成代谢疗法治疗骨质疏松症的成骨潜力。补充CAFG改善了长骨的骨小梁微结构，增加了椎体和股骨的生物力学强度参数，降低了骨转换指标，效果优于金雀异黄素。去卵巢小鼠口服CAFG可增加骨髓中的骨祖细胞，增加股骨中成骨基因的表达，并显示新的骨形成，而不出现子宫增生。CAFG通过抑制骨骼破骨细胞基因的表达，增加骨保护素的mRNA表达，抑制破骨细胞的激活。CAFG也是一种有效的软骨形成促进剂，从组织、细胞和基因水平对小鼠股骨钻孔伤后皮质骨的修复具有促进作用。在细胞水平上，CAFG促进成骨细胞的增殖、存活和分化。成骨细胞中的信号转导抑制物参与了骨形态发生蛋白2刺激的p-38丝裂原活化蛋白激酶通路，启动Wnt/β-连环蛋白信号转导，从而减少GSK3-β的磷酸化和随后的β-连环蛋白的核积聚。Wnt受体阻断剂Dkk1和Tcf复合体抑制剂FH535通过降低β-catenin水平来阻断成骨作用。CAFG调节骨髓间充质干细胞对骨形态发生蛋白2的反应性，通过Wnt/β-catenin机制促进成骨细胞分化。去卵巢小鼠每日1 剂量的CAFG(人剂量∼0.081 mg/kg)能促进骨形成，减少骨吸收和骨转换，优于众所周知的植物雌激素金雀异黄素。由于CAFG对骨的固有特性，它可以被定位为治疗绝经后骨质疏松症和骨折修复的潜在药物和食品补充剂。
Recently, we reported that extract of Dalbergia sissoo made from leaves and pods have antiresorptive and bone-forming effects. The positive skeletal effect attributed because of active molecules present in the extract of Dalbergia sissoo. Caviunin 7-O-[β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside] (CAFG), a novel isoflavonoid show higher percentage present in the extract. Here, we show the osteogenic potential of CAFG as an alternative for anabolic therapy for the treatment of osteoporosis by stimulating bone morphogenetic protein 2 (BMP2) and Wnt/β-catenin mechanism. CAFG supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur and decreased bone turnover markers better than genistein. Oral administration of CAFG to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased the expression of osteogenic genes in femur and show new bone formation without uterine hyperplasia. CAFG increased mRNA expression of osteoprotegerin in bone and inhibited osteoclast activation by inhibiting the expression of skeletal osteoclastogenic genes. CAFG is also an effective accelerant for chondrogenesis and has stimulatory effect on the repair of cortical bone after drill-hole injury at the tissue, cell and gene level in mouse femur. At cellular levels, CAFG stimulated osteoblast proliferation, survival and differentiation. Signal transduction inhibitors in osteoblast demonstrated involvement of p-38 mitogen-activated protein kinase pathway stimulated by BMP2 to initiate Wnt/β-catenin signaling to reduce phosphorylation of GSK3-β and subsequent nuclear accumulation of β-catenin. Osteogenic effects were abrogated by Dkk1, Wnt-receptor blocker and FH535, inhibitor of TCF-complex by reduction in β-catenin levels. CAFG modulated MSC responsiveness to BMP2, which promoted osteoblast differentiation via Wnt/β-catenin mechanism. CAFG at 1 mg/kg/day dose in ovariectomy mice (human dose ∼0.081 mg/kg) led to enhanced bone formation, reduced bone resorption and bone turnover better than well-known phytoestrogen genistein. Owing to CAFG's inherent properties for bone, it could be positioned as a potential drug, food supplement, for postmenopausal osteoporosis and fracture repair.