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Bone Morphogenetic Protein 4 Gene Therapy in Mice Inhibits Myeloma Tumor Growth, But Has a Negative Impact on Bone.

Published on Jan 1, 2020
· DOI :10.1002/JBM4.10247
Marita Westhrin5
Estimated H-index: 5
(NTNU: Norwegian University of Science and Technology),
Toril Holien16
Estimated H-index: 16
(NTNU: Norwegian University of Science and Technology)
+ 13 AuthorsTherese Standal16
Estimated H-index: 16
(NTNU: Norwegian University of Science and Technology)
Abstract
Multiple myeloma is characterized by accumulation of malignant plasma cells in the bone marrow. Most patients suffer from an osteolytic bone disease, caused by increased bone degradation and reduced bone formation. Bone morphogenetic protein 4 (BMP4) is important for both pre- and postnatal bone formation and induces growth arrest and apoptosis of myeloma cells. BMP4-treatment of myeloma patients could have the potential to reduce tumor growth and restore bone formation. We therefore explored BMP4 gene therapy in a human-mouse model of multiple myeloma where humanized bone scaffolds were implanted subcutaneously in RAG2(-/-) gammaC(-/-)mice. Mice were treated with adeno-associated virus serotype 8 BMP4 vectors (AAV8-BMP4) to express BMP4 in the liver. When mature BMP4 was detectable in the circulation, myeloma cells were injected into the scaffolds and tumor growth was examined by weekly imaging. Strikingly, the tumor burden was reduced in AAV8-BMP4 mice compared with the AAV8-CTRL mice, suggesting that increased circulating BMP4 reduced tumor growth. BMP4-treatment also prevented bone loss in the scaffolds, most likely due to reduced tumor load. To delineate the effects of BMP4 overexpression on bone per se, without direct influence from cancer cells, we examined the unaffected, non-myeloma femurs by muCT. Surprisingly, the AAV8-BMP4 mice had significantly reduced trabecular bone volume, trabecular numbers, as well as significantly increased trabecular separation compared with the AAV8-CTRL mice. There was no difference in cortical bone parameters between the two groups. Taken together, BMP4 gene therapy inhibited myeloma tumor growth, but also reduced the amount of trabecular bone in mice. Our data suggest that care should be taken when considering using BMP4 as a therapeutic agent. (c) 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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References38
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#1Oddrun Elise Olsen (NTNU: Norwegian University of Science and Technology)H-Index: 7
#2Meenu Sankar (University of Skövde)H-Index: 1
Last. Toril Holien (NTNU: Norwegian University of Science and Technology)H-Index: 16
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TGF-β/BMP superfamily ligands require heteromeric complexes of type 1 and 2 receptors for ligand dependent downstream signaling. Activin A, a TGF-β superfamily member, inhibits growth of multiple myeloma cells, but the mechanism is unknown. We aimed to clarify how activins affect myeloma cell survival. Activin A activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor, but may also activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. We demonstrate that ac...
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Multiple myeloma (MM) is a plasma cell neoplasm that accounts for 2% of all haematological malignancies and predominantly affects older individuals (with a median age at diagnosis of 65–70 years). MM is consistently preceded by the clinically recognized precancerous stages monoclonal gammopathy of undetermined significance and smouldering MM. Thus far, MM has been considered as a single disease entity, but the clinical presentation, response to treatment, and survival outcomes of patients with M...
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Summary We examined the effect of Bone Morphogenetic Protein 4 (BMP4) on energy expenditure in adult mature mice by targeting the liver with adeno-associated viral (AAV) BMP4 vectors to increase circulating levels. We verified the direct effect of BMP4 in inducing a brown oxidative phenotype in differentiating preadipocytes in vitro. AAV-BMP4-treated mice display marked browning of subcutaneous adipocytes, with increased mitochondria and Uncoupling Protein 1 (UCP1). These mice are protected from...
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