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

骨髓瘤骨病(MBD)是一种发生在浆细胞疾病多发性骨髓瘤(MM)患者身上的衰弱骨骼疾病，可导致骨损伤、骨折和骨重建受损。在MBD中，骨髓间充质基质细胞(MSC)表现出向成脂分化的转变，而成骨分化受损。随着多发性骨髓瘤骨髓脂肪组织(BMAT)的增加，肥胖是多发性骨髓瘤的危险因素，因为成脂分化增加可能支持肿瘤生长并抑制成骨。骨的机械负荷诱导间充质干细胞和成骨细胞的机械转导，刺激成骨分化和骨生长。在MBD的小鼠模型中，我们已经证明，对带有MM的后肢进行机械负荷是对抗肿瘤生长和诱导骨再生的一种对策。在这个新的项目中，我们将调查患有多发性骨髓瘤和高BMAT的小鼠是否同样从机械负荷(2g超重力)中受益，以及机械卸荷是否是导致骨质疏松症的另一个危险因素。我们将描述骨骼微结构，分析肿瘤生长和大小，测量血清参数，在2D和3D细胞培养模型中验证我们的结果，并将我们的发现与患者数据相关联。将提出以下假设：在患有MBD的肥胖小鼠中，机械负荷(A)恢复了骨表型，(B)减少了多发性骨髓瘤的肿瘤负担，(C)在骨细胞中具有改变的转录和表观遗传特征。这个两国项目结合了三个法国PI(骨骼、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，我们的结果将有助于理解MBD在受损的骨髓和骨髓中的进展，以及在代谢挑战条件下机械加减负荷的影响。

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.