Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

Jing Fu, Shirong Li, Rentian Feng, Huihui Ma, Farideh Sabeh, G David Roodman, Ji Wang, Samuel Robinson, X Edward Guo, Thomas Lund, Daniel Normolle, Markus Y Mapara, Stephen J Weiss, Suzanne Lentzsch

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Abstrakt

Multiple myeloma (MM) cells secrete osteoclastogenic factors that promote osteolytic lesions; however, the identity of these factors is largely unknown. Here, we performed a screen of human myeloma cells to identify pro-osteoclastogenic agents that could potentially serve as therapeutic targets for ameliorating MM-associated bone disease. We found that myeloma cells express high levels of the matrix metalloproteinase MMP-13 and determined that MMP-13 directly enhances osteoclast multinucleation and bone-resorptive activity by triggering upregulation of the cell fusogen DC-STAMP. Moreover, this effect was independent of the proteolytic activity of the enzyme. Further, in mouse xenograft models, silencing MMP-13 expression in myeloma cells inhibited the development of osteolytic lesions. In patient cohorts, MMP-13 expression was localized to BM-associated myeloma cells, while elevated MMP-13 serum levels were able to correctly predict the presence of active bone disease. Together, these data demonstrate that MMP-13 is critical for the development of osteolytic lesions in MM and that targeting the MMP-13 protein - rather than its catalytic activity - constitutes a potential approach to mitigating bone disease in affected patients.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Investigation
Vol/bind126
Udgave nummer5
Sider (fra-til)1759-1772
ISSN0021-9738
DOI
StatusUdgivet - 2016

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