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Reevaluation of osteoporosis therapies based on the site-specificresponse of bone cells derived from lower limb, mandibular and calvarial bones to mechanical stimuli.

根据下肢、下颌骨和颅骨来源的骨细胞对机械刺激的位点特异性反应重新评估骨质疏松症治疗。

基本信息

批准号：
22616009
负责人：
MIKUNI-TAKAGAKI Yuko
金额：
$ 3万
依托单位：
Kanagawa Dental College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

While astronauts and bed-rest patients lose weight-bearing bone by almost one percent a month, non-weight-bearing bone is insensitive to unloading. It is unclear how bone cells at different sites detect mechanical loading/unloading and how site-specific mechanotransduction affects bone homeostasis. The aim of this study is to re-evaluate our understanding of osteoporosis and its treatment in terms of the response to the mechanical environment by bone cells at different sites. To differentiate the anabolic mechanical response of mandibular cells from those of calvarial and long-bone cells, we isolated mouse osteoblasts and subjected them to therapeutic low intensity pulsed ultrasound (LIPUS). Our results showed the following:1. While LIPUS-accelerated differentiation is universal among the osteoblasts ofdifferent origin, the mandible needs mechanical stimuli for RANKL expression/remodeling and survival.2. In mandibular and long-bone osteoblasts, ILK lies upstream of PI3K/Akt but downstr … More eam from α5β1 integrin, which is indispensable for the response to LIPUS.3. In calvaria, the up-regulation by LIPUS is not significant except in β-catenin.While the calvaria shares ectodermal origin with the mandibular bone, it may notneed mechanotransduction for such anabolic reactions.4. In mandible, anti-α5β1 Ab completely blocks the up-regulation of LIPUS.5. The role of α5β1 integrin as a gate keeper may have evolved to protect jaw bones from unfavorable responses to the inflammatory cytokines arising from periodontal pathology in the absence of mechanical stimuli.These findings indicate that the cellular environment, in addition to the tridermic origin, determines site-specific bone homeostasis through the remodeling of bone and the survival of osteoblasts. Differentiated cells of the osteoblastic lineage at different bone sites transmit signals through transmembrane integrins such as α5β1 integrin in case of mandibular osteoblasts, whose signaling pathways are influenced by environmental factors such as inflammatory cytokines produced in response to bacteria. To further delineate the unique oral mechanical defense system, which we believe may fail by bisphosphonate administration resulting in osteonecrosis of the jaw (ONJ), we developed a rat ONJ model that was subjected to LIPUS, which provided an alternative mechanical stress for the biting force. As a result, we were able to show the efficacy of LIPUS, which prevented the onset of ONJ in themodel system we developed. Less

虽然宇航员和卧床休息的病人每月损失近1%的承重骨，但非承重骨对卸载不敏感。目前尚不清楚不同部位的骨细胞如何检测机械加载/卸载，以及特定部位的机械转导如何影响骨稳态。本研究的目的是根据不同部位骨细胞对机械环境的反应来重新评估我们对骨质疏松症及其治疗的理解。为了区分下颌骨细胞与颅骨和长骨细胞的合成代谢力学反应，我们分离小鼠成骨细胞并将其置于治疗性低强度脉冲超声（LIPUS）下。我们的研究结果表明：1。虽然lipus加速分化在不同来源的成骨细胞中是普遍存在的，但下颌骨需要机械刺激来促进RANKL的表达/重塑和存活。在下颌骨和长骨成骨细胞中，ILK位于PI3K/Akt的上游，但位于α5β1整合素的下游，而α5β1整合素对于lipus的应答是必不可少的。在calvaria中，LIPUS除上调β-catenin外，其余均不显著上调。虽然颅骨与下颌骨有相同的外胚层起源，但它可能不需要机械转导来进行这种合成代谢反应。在下颌骨，抗α5β1 Ab完全阻断lipus的上调。α5β1整合素作为看门人的作用可能已经进化到保护颌骨在缺乏机械刺激的情况下免受牙周病理引起的炎症细胞因子的不利反应。这些发现表明，细胞环境，除了三缘起源，通过骨的重塑和成骨细胞的存活，决定了特定位点的骨稳态。成骨细胞系在不同骨位点的分化细胞通过α5β1整合素等跨膜整合素传递信号，而下颌骨成骨细胞的信号通路受细菌应答产生的炎症因子等环境因素的影响。为了进一步描述独特的口腔机械防御系统，我们认为双膦酸盐可能会导致颌骨骨坏死（ONJ），我们开发了一个受到LIPUS的大鼠ONJ模型，LIPUS为咬合力提供了另一种机械应力。因此，我们能够证明LIPUS的有效性，它可以在我们开发的模型系统中阻止ONJ的发生。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

顎骨壊死モデルラット作成とLIPUSによる防止の試み

建立大鼠颌骨坏死模型并尝试使用 LIPUS 预防它

DOI：
发表时间：
2013
期刊：
影响因子：
0
作者：
野田和恵;種村留美;長尾徹;L. Borell; P. Bontje;田中隆博,渡部弘隆,河田亮,佐藤武則,船山祐太,田島愛弓,浜田信城,石井信之,寺中敏夫,高垣裕子
通讯作者：
田中隆博,渡部弘隆,河田亮,佐藤武則,船山祐太,田島愛弓,浜田信城,石井信之,寺中敏夫,高垣裕子

Low Intensity Pulsed Ultrasound Accelerates Delayed Healing Process by Reducing the Time Required for the Completion of Endochondral Ossification in the Aged Mouse Femur Fracture Model

DOI：
10.1538/expanim.60.385
发表时间：
2011-07-01
期刊：
EXPERIMENTAL ANIMALS
影响因子：
2.4
作者：
Katano, Motoaki;Naruse, Kouji;Urabe, Ken
通讯作者：
Urabe, Ken

Low-intensity pulsed ultrasound promotes the osteogenic effectinduced by bone allograft

低强度脉冲超声促进同种异体骨移植的成骨作用

DOI：
发表时间：
2011
期刊：
Kitasato Med J
影响因子：
0
作者：
Aikawa J,Naruse K,Uchida K,Katano M;Mikuni-Takagaki Y;Kozai Y;Kashima I;Takaso M,ltoman M,Urabe K
通讯作者：
Takaso M,ltoman M,Urabe K

Is Alendronate Effective in Improving Material Properties of Frail Cortical Bone in Inactive Model Rats

阿仑膦酸钠能否有效改善不活动模型大鼠脆弱皮质骨的材料性能