Publication Date:
2018-11-29
Description:
TH and MW contributed equally to this work. Background Multiple myeloma is caused by an accumulation of malignant plasma cells in the bone marrow. Myeloma is characterized by an osteolytic bone disease, caused by increased bone degradation and reduced bone formation. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-β superfamily. BMP-signaling is important for both pre- and postnatal bone formation. Additionally, several BMPs induce growth arrest and apoptosis in myeloma cells. Thus, increasing BMP-signaling in myeloma patients may reduce tumor growth and restore bone formation. We therefore explored BMP4 gene therapy in a human-mouse model of multiple myeloma. Methods Calcium phosphate scaffolds with human mesenchymal stromal cells (MSCs) were implanted in RAG2-/-GC-/- mice and the MSCs were left to differentiate in vivo for 8 weeks to create a humanized bone microenvironment. Then, adeno-associated virus (AAV), AAV8-BMP4, which has tropism for liver cells and expresses murine Bmp4 under the control of the liver specific human α1-antitrypsin (hAAT1) promoter, were administered by tail-vein injection. Empty viral vectors, AAV8-CTRL, were used for the control group. After 2 weeks, when BMP4 was detectable in circulation, we injected fluorescently labelled KJON myeloma cells in 3 out of 4 scaffolds in each mouse. The KJON cells are hyperdiploid, have a relatively slow growth rate and rely on interleukin (IL)-6 supplementation in the absence of a supporting microenvironment, thus resembling primary human myeloma cells. Tumor growth was examined by weekly imaging until end-point, 6 weeks after tumor cell injection. Results At end-point, serum levels of BMP4 in AAV8-BMP4 mice were in the range of 50-200 ng/mL, but not detectable in AAV8-CTRL mice. Strikingly, tumor growth as quantified by imaging was significantly reduced in AAV8-BMP4 mice compared with the AAV8-CTRL mice (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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