Molecular mechanisms, current management and next generation therapy in myeloma bone disease

Heusschen, Roy; Muller, Joséphine; Duray, Elodie; Withofs, Nadia; Bolomsky, Arnold; Baron, Frédéric; Béguin, Yves; Menu, Eline; Ludwig, Heinz; Caers, Jo

doi:10.1080/10428194.2017.1323272

Cited by 18 publications

(21 citation statements)

References 159 publications

(179 reference statements)

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“…At the time of diagnosis, osteolytic lesions are present in 60% of patients. In addition, almost every patient will manifest a lytic lesion at some point during their disease course, resulting in increased morbidity and pain with ultimately a severe impact on the quality of life 1 – 3 .…”

Section: Introductionmentioning

confidence: 99%

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts

Faict

Muller

Veirman

et al. 2018

Blood Cancer Journal

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117

114

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Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or ‘exosomes’, not only enhanced osteoclast activity, they also blocked osteoblast differentiation and functionality in vitro. Mechanistically, we could demonstrate that transfer of DKK-1 led to a reduction in Runx2, Osterix, and Collagen 1A1 in osteoblasts. In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. Blocking exosome secretion using the sphingomyelinase inhibitor GW4869 not only increased cortical bone volume, but also it sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response when GW4869 and bortezomib were combined. Altogether, our results indicate an important role for exosomes in the BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy.

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Section: Introductionmentioning

confidence: 99%

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts

Faict

Muller

Veirman

et al. 2018

Blood Cancer Journal

Self Cite

117

114

View full text Add to dashboard Cite

show abstract

“…In that study, IL‐32 mediated the NF‐kB nuclear translocation resulting in the stimulation of osteoclastic activation and differentiation. Bone resorption is triggered by the release of molecules, including sFRP2 and DKK‐1, inhibitors of the Wnt pathway, resulting in an inhibition in osteoblast differentiation and proliferation . So far, no studies have assessed MM EVs effects on the functionality of osteoblast as well as suppressing exosome secretion impacts in the MM microenvironment.…”

Section: Exosomes and MMmentioning

confidence: 99%

“…The prevention and treatment of MM bone disease (MMBD) must be further focused in MM. Nowadays; the standard therapy for MMBD mostly focuses on OCs suppression by administering bisphosphonates . While, these drugs do not possess any direct impact on bone formation, but relatively suppress general bone turnover.…”

Section: Exosomes and MMmentioning

confidence: 99%

“…Bone resorption is triggered by the release of molecules, including sFRP2 and DKK-1, inhibitors of the Wnt pathway, resulting in an inhibition in osteoblast differentiation and proliferation. 114 So far, no studies have assessed MM EVs effects on the functionality of osteoblast as well as suppressing exosome secretion impacts in the MM microenvironment. The prevention and treatment of MM bone disease (MMBD) must be further focused in MM.…”

Section: Exosomes and MMmentioning

confidence: 99%

“…Nowadays; the standard therapy for MMBD mostly focuses on OCs suppression by administering bisphosphonates. 114 While, these drugs do not possess any direct impact on bone formation, but relatively suppress general bone turnover. Hence, finding novel targets that decrease tumor growth through interfering in BM microenvironment is an urgent issue.…”

Section: Exosomes and MMmentioning

confidence: 99%

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MicroRNAs and exosomes: Small molecules with big actions in multiple myeloma pathogenesis

et al. 2019

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Multiple myeloma (MM), an incurable hematologic malignancy of plasma cells increasing in the bone marrow (BM), has a complex microenvironment made to support proliferation, survival, and drug resistance of tumor cells. MicroRNAs (miRNAs), short non‐coding RNAs regulating genes expression at posttranscriptional level, have been indicated to be functionally deregulated or abnormally expressed in MM cells. Moreover, by means of miRNAs, tumor microenvironment also modulates the function of MM cells. Consistently, it has been demonstrated that miRNA levels regulation impairs their interaction with the microenvironment of BM as well as create considerable antitumor feature even capable of overcoming the protective BM milieu. Communication between cancer stromal cells and cancer cells is a key factor in tumor progression. Finding out this interaction is important to develop effective approaches that reverse bone diseases. Exosomes, nano‐vehicles having crucial roles in cell‐to‐cell communication, through targeting their cargos (i.e., miRNAs, mRNAs, DNAs, and proteins), are implicated in MM pathogenesis.

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Oscillating Fluid Flow Activated Osteocyte Lysate‐Based Hydrogel for Regulating Osteoblast/Osteoclast Homeostasis to Enhance Bone Repair

Zheng

Zhou

et al. 2023

Advanced Science

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As major regulators on bone formation/resorption in response to mechanical stimuli, osteocytes have shown great promise for restoring bone injury. However, due to the unmanageable and unabiding cell functions in unloading or diseased environments, the efficacy of osteogenic induction by osteocytes has been enormously limited. Herein, a facile method of oscillating fluid flow (OFF) loading for cell culture is reported, which enables osteocytes to initiate only osteogenesis and not the osteolysis process. After OFF loading, multiple and sufficient soluble mediators are produced in osteocytes, and the collected osteocyte lysates invariably induce robust osteoblastic differentiation and proliferation while restraining osteoclast generation and activity under unloading or pathological conditions. Mechanistic studies confirm that elevated glycolysis and activation of the ERK1/2 and Wnt/𝜷-catenin pathways are the major contributors to the initiation of osteoinduction functions induced by osteocytes. Moreover, an osteocyte lysate-based hydrogel is designed to establish a stockpile of "active osteocytes" to sustainably deliver bioactive proteins, resulting in accelerated healing through regulation of endogenous osteoblast/osteoclast homeostasis.

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Molecular mechanisms, current management and next generation therapy in myeloma bone disease

Cited by 18 publications

References 159 publications

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts

MicroRNAs and exosomes: Small molecules with big actions in multiple myeloma pathogenesis

Oscillating Fluid Flow Activated Osteocyte Lysate‐Based Hydrogel for Regulating Osteoblast/Osteoclast Homeostasis to Enhance Bone Repair

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