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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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1759-1772
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number5
DOIs
StatePublished - May 2 2016

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Osteoclasts
Matrix Metalloproteinases
Multiple Myeloma
Bone Diseases
Matrix Metalloproteinase 13
Heterografts
Peptide Hydrolases
Up-Regulation
Bone and Bones
Serum
Proteins

ASJC Scopus subject areas

  • Medicine(all)

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Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease. / Fu, Jing; Li, Shirong; Feng, Rentian; Ma, Huihui; Sabeh, Farideh; Roodman, G. David; Wang, Ji; Robinson, Samuel; Guo, X. Edward; Lund, Thomas; Normolle, Daniel; Mapara, Markus Y.; Weiss, Stephen J.; Lentzsch, Suzanne.

In: Journal of Clinical Investigation, Vol. 126, No. 5, 02.05.2016, p. 1759-1772.

Research output: Contribution to journalArticle

Fu, J, Li, S, Feng, R, Ma, H, Sabeh, F, Roodman, GD, Wang, J, Robinson, S, Guo, XE, Lund, T, Normolle, D, Mapara, MY, Weiss, SJ & Lentzsch, S 2016, 'Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease', Journal of Clinical Investigation, vol. 126, no. 5, pp. 1759-1772. https://doi.org/10.1172/JCI80276
Fu, Jing ; Li, Shirong ; Feng, Rentian ; Ma, Huihui ; Sabeh, Farideh ; Roodman, G. David ; Wang, Ji ; Robinson, Samuel ; Guo, X. Edward ; Lund, Thomas ; Normolle, Daniel ; Mapara, Markus Y. ; Weiss, Stephen J. ; Lentzsch, Suzanne. / Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 5. pp. 1759-1772.
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