Adaptive response of bone to mechanical strain in a mouse model of myeloma bone disease
Final Report Abstract
Multiple myeloma is a malignant plasma cell disorder, in which tumor cells spread and accumulate in the bone marrow. Myeloma cells inhibit osteoblast function and induce osteoclast activity, subsequently inducing disseminated (osteoporosis) and localized (osteolytic lesions) bone disease. In this respect multiple myeloma can serve as a blueprint for other osteotropic tumors such as breast and prostate cancer. Among the patients diagnosed with multiple myeloma, 80% are seen late in the development of myeloma bone disease with symptoms of severe pain and fractures. Morbidity and mortality are high and quality of life is significantly affected by MM bone disease. To date antiresorptive pharmacological treatment of myeloma bone disease with bisphosphonates or the receptor activator of NF-kB ligand antibody denosumab, has not succeeded in regenerating bone tissue even in the absence of signs of active disease. While anabolic treatment of bone disease in malignancies is still a matter of discussion, a promising non-pharmacological approach to prevent or rescue osteopenia is the use of well-controlled physical stimuli. Despite the increased fracture risk in myeloma patients, physical exercise such as aerobic and strength training has been shown to be safe in this patient population. In this study we demonstrated in the MOPC315.BM.Luc model for myeloma bone disease that physical stimuli in the form of mechanical loading have a promising bone-sparing outcome. Physical stimuli even mitigated tumor cell growth and dissemination. High-throughput transcriptome profiling of cortical osteocytes in the myeloma model revealed that tumor establishment in the bone microenvironment caused substantial alterations of gene regulation as did physical stimulation. We further identified genes that were downregulated in cortical osteocytes by myeloma invasion and were counterregulated by loading. We found that extracellular matrix-related genes were significantly downregulated and this gene set was rescued or stimulated by mechanical loading. Cortical osteocytes and myeloma cells communicate and thereby generate a tumor supportive microenvironment. Part of this mutual interaction is the expression and secretion of common ECM- related factors from both cell types. In a collaboration with Regina Ebert (University of Würzburg) we identified ECM and adhesion-related genes which are differentially expressed in MM cells based on their adhesion strength to bone precursor cells such as mesenchymal stem cells. We identified a partial overlap between the in vivo and in vitro gene sets representing a convincing interactive gene network in which candidates belong to three clusters of (1) skeletal development, (2) lipid transport and (3) extracellular matrix organization. In addition, we found that low expression of lead candidates from this network like the low-density lipoprotein receptor-related protein 1 is associated with worse myeloma patient survival using large cohorts of clinically derived microarray data. In a follow-up study we will molecularly dissect the networks behind mechanotransduction and tumor homing and spread, searching for effective types of mechanical loading and innovative druggable targets that address the bone anabolic and anti-tumor effects. This will allow for identifying targets in models of mechanical loading that can be addressed to reconstitute healthy bone tissue and at the same time impart antitumor effects in the microenvironment.
Publications
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(2019) Nanogels enable efficient miRNA delivery and target gene downregulation in transfection-resistant multiple myeloma cells. Biomacromolecules, 20:916-926
Zilkowski I, Ziouti F, Schulze A, Hauck S, Schmidt S, Mainz L, Sauer M, Albrecht K, Jundt F, Groll J
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(2019) Notch signaling is activated through mechanical strain in human bone marrow-derived mesenchymal stromal cells. Stem Cells Int., 2019:5150634
Ziouti F, Ebert R, Rummler M, Krug M, Müller-Deubert S, Lüdemann M, Jakob F, Willie BM, Jundt F
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(2020) An early myeloma bone disease model in skeletally-mature mice as a platform for biomaterial characterization of the extracellular matrix. J. Oncol., 2020:3985315
Ziouti F, Prates Soares A, Moreno-Jiménez I, Rack A, Bogen B, Cipitria A, Zaslansky P, Jundt F
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(2020) Impact of whole-body vibration exercise on physical performance and bone turnover in patients with monoclonal gammopathy of undetermined significance. J Bone Oncol., 25:100323
Seefried L, Genest F, Strömsdörfer J, Engelmann B, Lapa C, Jakob F, Baumann FT, Sperlich B, Jundt F
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(2020) Interactions between Muscle and Bone-Where Physics Meets Biology. Biomolecules, 10:432
Herrmann M, Engelke K, Ebert R, Müller-Deubert S, Rudert M, Ziouti F, Jundt F, Felsenberg D, Jakob F
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(2021) Mechanical loading prevents bone destruction and exerts anti-tumor effects in the MOPC315.BM.Luc model of myeloma bone disease. Acta Biomater., 119:247-258
Rummler M, Ziouti F, Bouchard AL, Brandl A, Duda GN, Bogen B, Beilhack A, Lynch ME, Jundt F, Willie BM,
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(2021) Prevention of bone destruction by mechanical loading is not enhanced by the bruton’s tyrosine kinase inhibitor CC-292 in myeloma bone disease. Int. J. Mol. Sci., 22:3840
Ziouti F, Rummler M, Steyn B, Thiele T., Seliger A., Duda G.N., Bogen, B., Willie, B.M., Jundt, F
