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

虽然宇航员和卧床休息的病人每月会失去近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/卸载以及部位特异性机械转导如何影响骨稳态。本研究的目的是重新评估我们对骨质疏松症及其治疗的理解，即不同部位骨细胞对机械环境的反应。为了区分下颌骨细胞的合成代谢的机械反应，从颅骨和长骨细胞，我们分离小鼠成骨细胞，并进行治疗性低强度脉冲超声（LIPUS）。结果表明：1.虽然LIPUS加速分化在不同来源的成骨细胞中具有普遍性，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PI 3 K/Akt的上游，但位于PI 3 K/Akt的下游。 关于我们 eam来自α5β1整合素，其是LIPUS应答所必需的.在颅盖骨中，LIPUS的上调除了β-catenin外并不显著.虽然颅盖骨与下颌骨共享外胚层起源，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.α5β1整合素作为一个守门人的角色可能已经进化到保护颌骨免受牙周病引起的炎症细胞因子在没有机械刺激的情况下的不利反应。这些发现表明，除了三胚层起源，细胞环境通过骨的重塑和成骨细胞的存活来决定特定部位的骨稳态。在不同骨部位的成骨细胞谱系的分化细胞通过跨膜整合素（例如在下颌骨成骨细胞的情况下的α5β1整合素）传递信号，其信号传导途径受到环境因素（例如响应于细菌产生的炎性细胞因子）的影响。为了进一步描述独特的口腔机械防御系统，我们认为这可能会失败的双膦酸盐管理导致骨坏死的颌骨（ONJ），我们开发了一个大鼠ONJ模型，进行LIPUS，这提供了一个替代的机械应力的咬合力。因此，我们能够证明LIPUS的有效性，它可以防止我们开发的模型系统中ONJ的发作。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