Mechanical loading prevents bone destruction and exerts anti-tumor effects in the MOPC315.BM.Luc model of myeloma bone disease

Rummler, Maximilian; Ziouti, Fani; Bouchard, Alice L.; Brandl, Andreas; Duda, Georg N.; Bogen, Bjarne; Beilhack, Andreas; Lynch, Maureen E.; Jundt, Franziska; Willie, Bettina M.

doi:10.1016/j.actbio.2020.10.041

Cited by 15 publications

(7 citation statements)

References 65 publications

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“…In relation to previous work, currently this is the first study evaluating human bone biopsies at the microstructural level, and so we can only refer to similar work in preclinical setting. Indeed, our established mouse model of MM bone disease was assessed for ultrastructural characterization of the mineralized and nonmineralized ECM, particularly of the osteocyte LCN in early stages of the disease 27,[38][39][40] . Skeletally mature mice were injected with MM cells and the osteocyte LCN architecture was analyzed using advanced imaging techniques, such as high resolution microCT, synchrotron phase contrast-enhanced microCT and confocal laser scanning microscopy (CLSM) 27 .…”

Section: Discussionmentioning

confidence: 99%

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

Moreno-Jiménez,

Heinig,

Heras

et al. 2023

Preprint

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Osteocytes are bone-embedded cells connected via canaliculi and they regulate the bone resorption/formation balance. Osteocyte function is altered in skeletal disorders including cancer. Multiple myeloma (MM) is a hematological malignancy, whereby plasma cells disrupt the bone homeostasis and induce excessive resorption of the mineralized extracellular matrix (ECM), as evidenced by clinical computed tomography (CT). However, morphometric analyses of the mineralized ECM and bone microporosity are not yet performed in patients with MM, nor in the precursor conditions of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Here, we characterize changes in 3D osteocyte lacunar morphology in bone biopsy samples obtained from patients with MGUS, SMM and newly diagnosed MM, using high resolution microCT. In the small lacunae 20-900 um3 range, we found a trend for lower lacunar density and increasing 50% cutoff of the lacunar volume cumulative distribution for diseased samples. In the larger lacunae 900-3000 um3 range, we found significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group, though the differences were not statistically significant. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae morphology, which could be an indicator for impaired bone quality. Future studies are needed to show whether these are consistent within comparable anatomical sites and could serve as a diagnostic or prognostic marker.

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Section: Discussionmentioning

confidence: 99%

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

Moreno-Jiménez,

Heinig,

Heras

et al. 2023

Preprint

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“…In contrast, mechanical unloading induces RANKL expression by osteocytes to enhance osteoclast formation and activity and thereby decreasing bone mass. Rummler et al reported an interesting experiment with mechanical loading in MM animal models [ 64 ]. The knee and ankle were fixated and mechanical loading with repeated forced compression was applied to tibiae into which MM cells were inoculated.…”

Section: Mutual Interaction Between MM Cells and Bone Microenvironmentmentioning

confidence: 99%

Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents

et al. 2023

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Introduction Multiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM. Approach In this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease. Conclusions MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.

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“…For example, it was found that cyclic mechanical load could promote bone regeneration processes at the endosteal and periosteal surfaces to diminished multiple myeloma bone disease. [262] Applying external stress or strain to scaffold is the most common method for studying mechanical stimulation. [263][264][265][266] For instance, MSCs encapsulated in hydrogels exhibited the strongest chondrogenic differentiation after being subjected to periodic mechanical pressure and shear force.…”

Section: Cell Differentiationmentioning

confidence: 99%

Mechanistically Scoping Cell‐Free and Cell‐Dependent Artificial Scaffolds in Rebuilding Skeletal and Dental Hard Tissues

Xiang

et al. 2022

Advanced Materials

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Rebuilding mineralized tissues in skeletal and dental systems remains costly and challenging. Despite numerous demands and heavy clinical burden over the world, sources of autografts, allografts, and xenografts are far limited, along with massive risks including viral infections, ethic crisis, and so on. Per such dilemma, artificial scaffolds have emerged to provide efficient alternatives. To date, cell‐free biomimetic mineralization (BM) and cell‐dependent scaffolds have both demonstrated promising capabilities of regenerating mineralized tissues. However, BM and cell‐dependent scaffolds have distinctive mechanisms for mineral genesis, which makes them methodically, synthetically, and functionally disparate. Herein, these two strategies in regenerative dentistry and orthopedics are systematically summarized at the level of mechanisms. For BM, methodological and theoretical advances are focused upon; and meanwhile, for cell‐dependent scaffolds, it is demonstrated how scaffolds orchestrate osteogenic cell fate. The summary of the experimental advances and clinical progress will endow researchers with mechanistic understandings of artificial scaffolds in rebuilding hard tissues, by which better clinical choices and research directions may be approached.

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Mechanical loading prevents bone destruction and exerts anti-tumor effects in the MOPC315.BM.Luc model of myeloma bone disease

Cited by 15 publications

References 65 publications

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: from monoclonal gammopathy to newly diagnosed multiple myeloma

Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents

Mechanistically Scoping Cell‐Free and Cell‐Dependent Artificial Scaffolds in Rebuilding Skeletal and Dental Hard Tissues

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