Other
14 Authors
- Ma H,
- Li S,
- Fu J,
- Robinson S,
- Normolle D,
- Roodman GD,
- Feng R,
- Lentzsch S,
- Sabeh F,
- Wang J,
- Guo XE,
- Weiss SJ,
- Mapara MY,
- Lund T
| First Author | Fu J | Year | 2016 |
| Journal | J Clin Invest | Volume | 126 |
| Issue | 5 | Pages | 1759-72 |
| PubMed ID | 27043283 | Mgi Jnum | J:234804 |
| Mgi Id | MGI:5790899 | Doi | 10.1172/JCI80276 |
| Citation | Fu J, et al. (2016) Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease. J Clin Invest 126(5):1759-72 |
| abstractText | 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. |
