Novel oxysterols have pro-osteogenic and anti-adipogenic effects in vitro and induce spinal fusion in vivo.
Novel oxysterols have pro-osteogenic and anti-adipogenic effects in vitro and induce spinal fusion in vivo.
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DOI：
10.1002/jcb.23082
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发表时间：
2011-06
影响因子：
4
通讯作者：
Parhami, Farhad
中科院分区：
文献类型：
--
作者：
Johnson, Jared S.;Meliton, Vicente;Kim, Woo Kyun;Lee, Kwang-Bok;Wang, Jeffrey C.;Nguyen, KhanhLinh;Yoo, Dongwon;Jung, Michael E.;Atti, Elisa;Tetradis, Sotirios;Pereira, Renata C.;Magyar, Clara;Nargizyan, Taya;Hahn, Theodore J.;Farouz, Francine;Thies, Scott;Parhami, Farhad
通过骨诱导材料刺激骨形成在脊柱融合手术、骨折修复和骨质疏松症治疗中具有重要的临床意义。我们先前报道了特定的天然存在的氧固醇，包括20（S）-羟基胆固醇（20 S）诱导多能间充质细胞的成骨分化，同时抑制其成脂分化。本文报道了20 S的两个结构类似物Oxy 34和Oxy 49的特性，它们通过激活Hedgehog（Hh）信号通路诱导骨髓基质细胞（MSC）成骨分化并抑制其成脂分化。用Oxy 34或Oxy 49处理M2- 10 B4 MSC诱导成骨分化标志物Runx 2、Osterix（Osx）、碱性磷酸酶（ALP）、骨唾液蛋白（BSP）和骨钙素（OCN）的表达，以及ALP酶活性和稳健的矿化。氧化固醇与PPARγ激活剂曲格列酮（Tro）一起处理可抑制成脂基因PPARγ、LPL和aP 2的mRNA表达，并抑制脂肪细胞的形成。使用后外侧横突间大鼠脊柱融合模型评估Oxy 34和Oxy 49在体内刺激骨形成的功效。接受Oxy 34或Oxy 49胶原植入物的大鼠显示出与BMP 2/胶原植入物相当的成骨功效，如通过X射线照相术、MicroCT和手动检查所测量的。组织学分析显示，在融合块内通过氧化固醇和rhBMP 2形成小梁和皮质骨，在BMP 2诱导的骨中具有稳健的脂肪生成，并且在氧化固醇诱导的骨中脂肪细胞显著较少。这些数据表明，Oxy 34和Oxy 49是有效的新型骨诱导分子，可能是进一步开发和用于需要局部骨形成的骨科适应症的合适候选物。
Stimulation of bone formation by osteoinductive materials is of great clinical importance in spinal fusion surgery, repair of bone fractures, and in the treatment of osteoporosis. We previously reported that specific naturally occurring oxysterols including 20(S)-hydroxycholesterol (20S) induce the osteogenic differentiation of pluripotent mesenchymal cells, while inhibiting their adipogenic differentiation. Here we report the characterization of two structural analogs of 20S, Oxy34 and Oxy49, which induce the osteogenic and inhibit the adipogenic differentiation of bone marrow stromal cells (MSC) through activation of Hedgehog (Hh) signaling. Treatment of M2-10B4 MSC with Oxy34 or Oxy49 induced the expression of osteogenic differentiation markers Runx2, Osterix (Osx), alkaline phosphatase (ALP), bone sialoprotein (BSP) and osteocalcin (OCN), as well as ALP enzymatic activity and robust mineralization. Treatment with oxysterols together with PPARγ activator, troglitazone (Tro), inhibited mRNA expression for adipogenic genes PPARγ, LPL, and aP2, and inhibited the formation of adipocytes. Efficacy of Oxy34 and Oxy49 in stimulating bone formation in vivo was assessed using the posterolateral intertransverse process rat spinal fusion model. Rats receiving collagen implants with Oxy 34 or Oxy49 showed comparable osteogenic efficacy to BMP2/collagen implants as measured by radiography, MicroCT, and manual inspection. Histological analysis showed trabecular and cortical bone formation by oxysterols and rhBMP2 within the fusion mass, with robust adipogenesis in BMP2-induced bone and significantly less adipocytes in oxysterol-induced bone. These data suggest that Oxy34 and Oxy49 are effective novel osteoinductive molecules and may be suitable candidates for further development and use in orthopaedic indications requiring local bone formation.
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影响因子：
4.8
作者：
Heng, Sophea;Paule, Sarah;Nie, Guiying
通讯作者：
Nie, Guiying
影响因子：
4.7
作者：
Langenfeld, EM;Calvano, SE;Langenfeld, J
通讯作者：
Langenfeld, J
DOI：
10.1359/jbmr.091024
发表时间：
2010-04
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Kim WK;Meliton V;Tetradis S;Weinmaster G;Hahn TJ;Carlson M;Nelson SF;Parhami F
通讯作者：
Parhami F
影响因子：
4.8
作者：
Garrett, Mark P.;Kakarla, Udaya K.;Sonntag, Volker K. H.
通讯作者：
Sonntag, Volker K. H.
影响因子：
6.2
作者：
Kha, HT;Basseri, B;Parhami, F
通讯作者：
Parhami, F