Green, A.C. orcid.org/0000-0002-0175-1485, Lath, D. orcid.org/0000-0001-5454-9419, Hudson, K. et al. (8 more authors) (2019) TGFβ inhibition stimulates collagen maturation to enhance bone repair and fracture resistance in a murine myeloma model. Journal of Bone and Mineral Research, 34 (12). pp. 2311-2326. ISSN 0884-0431
Abstract
Multiple myeloma is a plasma cell malignancy that causes debilitating bone disease and fractures, in which TGFβ plays a central role. Current treatments do not repair existing damage and fractures remain a common occurrence. We developed a novel low tumour phase murine model mimicking the plateau phase in patients, as we hypothesized this would be an ideal time to treat with a bone anabolic. Using in vivo microCT we show substantial and rapid bone lesion repair (and prevention) driven by SD‐208 (TGFβ receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266‐GFP‐luc myeloma. We discovered that lesion repair occurred via an intramembranous fracture repair‐like mechanism and that SD‐208 enhanced collagen matrix maturation to significantly improve fracture resistance. Lesion healing was associated with VEGFA expression in woven bone, reduced osteocyte‐derived PTHrP, increased osteoblasts, decreased osteoclasts and lower serum TRACP‐5b. SD‐208 also completely prevented bone lesion development mice with aggressive JJN3 tumors, and was more effective than an anti‐TGFβ neutralizing antibody (1D11). We also discovered that SD‐208 promoted osteoblastic differentiation (and overcame the TGFβ‐induced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fracture‐resistance with SD‐208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 American Society for Bone and Mineral Research. This is an author-produced version of a paper subsequently published in Journal of Bone and Mineral Research. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Tumor-induced bone disease; TGFβ; anabolics; pre-clinical studies; collagen |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Engineering (Sheffield) > Department of Chemical and Biological Engineering (Sheffield) The University of Sheffield > Faculty of Engineering (Sheffield) > Department of Materials Science and Engineering (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number Bloodwise 12053 Sheffield Hospitals Charity Grant 153878 Yorkshire Cancer Research Equipment S311 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 15 Oct 2019 11:02 |
Last Modified: | 16 Dec 2021 13:49 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/jbmr.3859 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:152153 |