A novel osteogenic oxysterol compound for therapeutic development to promote bone growth: activation of hedgehog signaling and osteogenesis through smoothened binding.
A novel osteogenic oxysterol compound for therapeutic development to promote bone growth: activation of hedgehog signaling and osteogenesis through smoothened binding.
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DOI：
10.1002/jbmr.2213
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发表时间：
2014-08
影响因子：
6.2
通讯作者：
Parhami, Farhad
中科院分区：
文献类型：
--
作者：
Montgomery, Scott R.;Nargizyan, Taya;Meliton, Vicente;Nachtergaele, Sigrid;Rohatgi, Rajat;Stappenbeck, Frank;Jung, Michael E.;Johnson, Jared S.;Aghdasi, Bayan;Tian, Haijun;Weintraub, Gil;Inoue, Hirokazu;Atti, Elisa;Tetradis, Sotirios;Pereira, Renata C.;Hokugo, Akishige;Alobaidaan, Raed;Tan, Yanlin;Hahn, Theodor J.;Wang, Jeffrey C.;Parhami, Farhad
成骨因子常用于骨科以促进骨生长、促进骨折愈合和诱导脊柱融合。成骨氧化固醇是天然存在的分子，其显示在体外诱导成骨分化并在体内促进脊柱融合。本研究的目的是确定一个成骨氧固醇更适合于临床开发比以前报道的，并评估其能力，以促进体外成骨和脊柱融合在大鼠体内。在合成的100多种氧化固醇类似物中，Oxy 133在C3 H10 T1/2小鼠胚胎成纤维细胞和M2- 10 B4小鼠骨髓基质细胞中诱导成骨标志物Runx 2、osterix（OSX）、碱性磷酸酶（ALP）、骨唾液蛋白（BSP）和骨钙素（OCN）的显著表达。Oxy 133诱导的8×-Gli荧光素酶报告基因的激活、其与Smoothened的直接结合以及Hedgehog（Hh）通路抑制剂环巴胺对Oxy 133诱导的成骨作用的抑制，证明了Hh通路在介导对Oxy 133的成骨反应中的作用。Oxy 133不通过BMP或Wnt信号传导刺激骨生成。Oxy 133诱导OSX、BSP和OCN的表达，并刺激原代人间充质干细胞的稳健矿化。在体内，双侧脊柱融合通过软骨内骨化发生，4周后在融合部位用Oxy 133处理的动物中通过X线观察到融合，8周后通过手动评估、显微CT（μCT）和组织学证实，与重组人骨形态发生蛋白-2（rhBMP-2）的疗效相同。与rhBMP-2不同，Oxy 133不会诱导融合块中的脂肪形成，并导致更致密的骨，这由更大的BV/TV比和更小的小梁分离证明。研究结果表明，Oxy 133作为成骨分子具有显著的潜力，与先前研究的氧化固醇相比，其合成更容易，融合时间更短。小分子成骨氧化固醇可作为下一代骨合成代谢药物用于治疗开发。
Osteogenic factors are often used in orthopedics to promote bone growth, improve fracture healing, and induce spine fusion. Osteogenic oxysterols are naturally occurring molecules that were shown to induce osteogenic differentiation in vitro and promote spine fusion in vivo. The purpose of this study was to identify an osteogenic oxysterol more suitable for clinical development than those previously reported, and evaluate its ability to promote osteogenesis in vitro and spine fusion in rats in vivo. Among more than 100 oxysterol analogues synthesized, Oxy133 induced significant expression of osteogenic markers Runx2, osterix (OSX), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN) in C3H10T1/2 mouse embryonic fibroblasts and in M2-10B4 mouse marrow stromal cells. Oxy133-induced activation of an 8×-Gli luciferase reporter, its direct binding to Smoothened, and the inhibition of Oxy133-induced osteogenic effects by the Hedgehog (Hh) pathway inhibitor, cyclopamine, demonstrated the role of Hh pathway in mediating osteogenic responses to Oxy133. Oxy133 did not stimulate osteogenesis via BMP or Wnt signaling. Oxy133 induced the expression of OSX, BSP, and OCN and stimulated robust mineralization in primary human mesenchymal stem cells. In vivo, bilateral spine fusion occurred through endochondral ossification and was observed in animals treated with Oxy133 at the fusion site on xray after 4 weeks and confirmed with manual assessment, micro CT (μCT), and histology after 8 weeks, with equal efficiency to recombinant human bone morphogenetic protein-2 (rhBMP-2). Unlike rhBMP-2, Oxy133 did not induce adipogenesis in the fusion mass and resulted in denser bone evidenced by greater BV/TV ratio and smaller trabecular separation. Findings here suggest that Oxy133 has significant potential as an osteogenic molecule with greater ease of synthesis and improved time to fusion compared to previously studied oxysterols. Small molecule osteogenic oxysterols may serve as the next generation of bone anabolic agents for therapeutic development.
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影响因子：
14.8
作者：
Nedelcu, Daniel;Liu, Jing;Xu, Yangqing;Jao, Cindy;Salic, Adrian
通讯作者：
Salic, Adrian
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通讯作者：
Parhami, Farhad
影响因子：
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通讯作者：
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