Adaptive response of bone to mechanical strain in a mouse model of myeloma bone disease

骨骼适应不断变化的负荷（所谓的建模），并具有自我修复和更新（重塑）的能力。这些合成代谢过程使骨骼能够在很长一段时间内成功地执行其机械功能。骨骼对机械负荷的局部适应性反应在运动员训练中表现得最为显著。运动形式的机械负荷在癌症患者中进一步显示出有希望的结果，以保持骨结构强度并防止骨丢失。我们在多发性骨髓瘤（MM）骨疾病的MOPC315.BM小鼠模型中获得了初步数据，这些数据表明，在机械负荷条件下，已经建立的溶骨性病变减少。MM是美国和欧洲第二常见的血液肿瘤，具有特征性溶骨性骨结构变化。该项目的目标是机械生物学的理解，机械刺激如何影响（重新）建模过程中的骨肿瘤微环境中建立MM和MM骨疾病的发病过程。我们的研究结果将帮助我们确定机械刺激作为合成代谢疗法治疗MM骨病的疗效。我们假设，机械刺激将通过激活已知的骨（再）建模途径（如RANK/RANKL和Wnt）来增加骨形成并减少骨吸收，这些途径被骨中的MM细胞有害地改变。我们研究骨吸收途径Notch是否参与机械刺激后的机械转导。我们将专门研究单独的机械负荷以及与Notch抑制相结合如何控制MM骨（重建）建模过程。为了在体外分析机械转导，我们使用小规模生物反应器系统，并在机械应变条件下共培养人间充质干细胞和MM细胞。在已经建立溶骨性MM骨病后，以及在MM肿瘤植入和骨病发生的同时，将对MOPC315.BM小鼠定时给予无创体内受控机械负荷。将通过纵向体内microCT成像以及常规组织形态学分析研究MM期间骨（重建）对机械载荷的响应。将结合组织学、生物化学和分子遗传学方法分析骨（重建）建模过程的分子机制。这项研究将有助于从根本上了解MM骨病对机械刺激的反应中合成代谢骨适应的机械生物学和分子机制。从这些实验中获得的知识将有助于开发治疗和预防MM骨病的新合成代谢策略。

Bones adapt to changing loads (so-called modeling) and have the capacity for self-repair and renewal (remodeling). These anabolic processes allow bones to perform their mechanical functions successfully over long periods of time. Local adaptive responses of bones to mechanical loading have been demonstrated most dramatically in athletes under training. Mechanical loading in form of exercise has further shown promising results in cancer patients to maintain bone structural strength and to prevent bone loss. We have preliminary data in our MOPC315.BM mouse model for multiple myeloma (MM) bone disease which demonstrate that already established osteolytic lesions decrease under conditions of mechanical loading. MM is the second most common hematological neoplasia in the USA and Europe with characteristic osteolytic bone structure changes. The goal of this project is a mechano-biological understanding of how mechanical stimulation influences (re)modeling processes in the bone tumor microenvironment of established MM and during onset of MM bone disease. Our results will help us to determine the efficacy of mechanical stimulation as an anabolic therapy to treat MM bone disease. We hypothesize that mechanical stimulation will increase bone formation and decrease bone resorption by activating known bone (re)modeling pathways (such as RANK/RANKL and Wnt), which are deleteriously altered by MM cells in bone. We study whether the osteoresorptive pathway Notch is involved in mechanotransduction after mechanical stimulation. We will specifically investigate how mechanical loading alone and in combination with inhibition of Notch controls MM bone (re)modeling processes. For analysis of mechanotransduction in vitro we use a small scale bioreactor system and co-cultivate human mesenchymal stem cells and MM cells under conditions of mechanical strain. Noninvasive in-vivo controlled mechanical loading will be administered to MOPC315.BM mice tibiae after already established osteolytic MM bone disease and simultaneously while MM tumor engraftment and bone disease are occurring. The bone (re)modelling response to mechanical loading during MM will be investigated by longitudinal in vivo microCT imaging as well as conventional histomorphometric analysis. The molecular mechanisms of the bone (re)modelling processes will be analyzed using a combination of histological, biochemical and molecular genetic methods. This study will contribute to a fundamental understanding of the mechano-biological and molecular mechanisms of anabolic bone adaptation during MM bone disease in response to mechanical stimuli. The knowledge gained from these experiments will aid in the development of novel anabolic strategies for treating and preventing MM bone disease.