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

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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.