期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 5, 页码 1759-1772出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI80276
关键词
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资金
- American Society of Hematology (ASH) Bridge Grant Award
- NIH [R01 CA175313, R01 HL93716, R21 CA141426, R01 AR059679, R21 CA179017-01]
- VA Merit Review funds
- National Cancer Institute (NCI) [P30CA047904]
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.
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