| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2012: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Research Abstract |
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
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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
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