Impact of obesity and hyper/hypo-mechanical loading on myeloma bone disease

肥胖和高/低机械负荷对骨髓瘤骨病的影响

• 批准号: 530200354
• 负责人: Professorin Dr. Regina Ebert
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/530200354?language=en
• 关键词: Impact; obesity; hyper; hypo; mechanical

Bone lesions, bone fractures and impaired bone remodeling occur in myeloma bone disease (MBD), a debilitating skeletal condition developing in patients suffering from the plasma cell disorder multiple myeloma (MM). In MBD bone marrow derived mesenchymal stromal cells (MSC) display a shift towards adipogenic differentiation, while osteogenic differentiation is impaired. With its increased bone marrow adipose tissue (BMAT), obesity is a risk factor for MM, as increased adipogenic differentiation may support tumor growth and dampen osteogenesis. Mechanical loading of bone induces mechanotransduction in MSC and osteoblasts, being a stimulus for osteogenic differentiation and bone growth. In a mouse model for MBD we have shown that mechanical loading of a MM-bearing hindlimb is a countermeasure for tumor growth and induces bone regeneration. In this new project we will investigate whether mice with MM and high BMAT similarly benefit from mechanical loading (2g hypergravity) and whether mechanical unloading, leading to an osteoporotic bone phenotype, is an additional risk factor in this context. We will characterize bone microarchitecture, analyze tumor growth and size, measure serum parameters, validate our results in 2D and 3D cell culture models and correlate our findings to patient data. The following hypotheses will be addressed: in obese mice suffering from MBD, mechanical loading (a) restores the bone phenotype (b) reduces MM tumor burden and (c) has an altered transcriptional and epigenetic signature in bone cells. This binational project combines the complementary expertise of three French PI’s (bone, mouse loading and unloading models, metabolism, epigenetics) and two German PI’s (MBD/MM, mechanical loading, bone cell biology, mechanotransduction). Overall our results will contribute to the understanding of MBD progression in compromised bone and bone marrow and the impact of mechanical up- versus un-loading in metabolically challenged conditions.

骨髓瘤骨疾病（MBD）是一种在患有浆细胞疾病多发性骨髓瘤（MM）的患者中发展的使人衰弱的骨骼病症，骨病变、骨折和受损的骨重建发生在MBD中。在MBD中，骨髓间充质基质细胞（MSC）显示向成脂分化的转变，而成骨分化受损。随着骨髓脂肪组织（BMAT）的增加，肥胖是MM的危险因素，因为脂肪形成分化的增加可能支持肿瘤生长并抑制骨生成。骨的机械负荷诱导MSC和成骨细胞中的机械转导，是成骨分化和骨生长的刺激物。在MBD小鼠模型中，我们已经表明，机械负荷的MM轴承后肢是一个对策，肿瘤生长和诱导骨再生。在这个新项目中，我们将研究MM和高BMAT小鼠是否同样受益于机械负荷（2g超重），以及导致骨质疏松表型的机械卸载是否是这种情况下的额外风险因素。我们将表征骨微结构，分析肿瘤生长和大小，测量血清参数，验证我们在2D和3D细胞培养模型中的结果，并将我们的发现与患者数据相关联。将讨论以下假设：在患有MBD的肥胖小鼠中，机械负荷（a）恢复骨表型（B）降低MM肿瘤负荷和（c）改变骨细胞中的转录和表观遗传特征。这个两国项目结合了三个法国PI（骨，小鼠加载和卸载模型，代谢，表观遗传学）和两个德国PI（MBD/MM，机械加载，骨细胞生物学，机械转导）的互补专业知识。总体而言，我们的研究结果将有助于理解受损骨和骨髓中的MBD进展，以及代谢挑战条件下机械加载与卸载的影响。