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

虽然宇航员和卧床患者的负重骨骼每月减少近1%，但非负重骨骼对卸货不敏感。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的骨细胞对力学环境的反应，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，我们分离了小鼠成骨细胞，并对它们进行了治疗性低强度脉冲超声(LIPUS)。我们的结果如下：1.虽然LIPUS加速分化在不同来源的成骨细胞中普遍存在，但下颌骨需要机械刺激才能表达/重塑RANKL并存活。在下颌骨和长骨成骨细胞中，ILK位于PI3K/Akt的上游，但在…下游更多来自α5β1整合素的EAM，这对于LIPUS的应答是不可或缺的。在颅骨中，LIPUS的上调作用除β-连环蛋白外并不显著，虽然颅骨与下颌骨有共同的外胚层来源，但这种合成代谢反应可能不需要机械转导。在下颌骨中，抗α5β1抗体完全阻断LIPUS的上调。α-5-β-1整合素作为门控器的作用可能是为了在没有机械刺激的情况下保护颌骨免受牙周病理产生的炎性细胞因子的不利反应。这些发现表明，除了三层起源外，细胞环境还通过骨的重塑和成骨细胞的存活来决定局部的骨稳态。在下颌骨成骨细胞中，不同部位的成骨细胞系分化的细胞通过跨膜整合素如α5β1整合素传递信号，其信号通路受环境因素的影响，如细菌反应产生的炎性细胞因子。为了进一步描述独特的口腔机械防御系统，我们认为双膦酸盐给药可能会导致颌骨坏死(ONJ)，我们建立了一种受到LIPUS的大鼠ONJ模型，该模型为咬合力提供了另一种机械应力。结果，我们能够展示LIPUS的有效性，它在我们开发的模型系统中预防了ONJ的发生。较少

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