Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease
Jing Fu, … , Stephen J. Weiss, Suzanne Lentzsch
Jing Fu, … , Stephen J. Weiss, Suzanne Lentzsch
Published April 4, 2016
Citation Information: J Clin Invest. 2016;126(5):1759-1772. https://doi.org/10.1172/JCI80276.
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Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

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.

Authors

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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Figure 1

Cell-autonomous and BMSC-dependent regulation of MMP-13 in MM cells.

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Cell-autonomous and BMSC-dependent regulation of MMP-13 in MM cells. (A)...
(A) MMP protein expression levels in human RPMI 8266 MM cells as determined by Luminex assay (mean ± SD; n = 3). (B) BMSCs were isolated from patients with MM and cultured with RPMI 8226 cells in direct contact (Contact) or in Transwell dishes (TW). MMP-13 concentrations in cell-free supernatants were determined by immunoassay (mean ± SD; n = 3). Data are representative of 2 independent experiments. **P ≤ 0.01, by ANOVA. (C) GFP+ RPMI 8226 cells were cocultured with BMSCs in direct contact or in Transwell dishes. MMP13 mRNA expression in RPMI 8226 cells was determined by qRT-PCR after separating GFP– BMSCs and GFP+ RPMI 8266 cells by flow cytometry. Data represent the mean ± SD (n = 3) and are representative of 2 independent experiments. **P ≤ 0.01, by ANOVA. (D) MM cell lines were cultured with or without CM prepared from BMSCs and a neutralizing Ab directed against IL-6 (5 μg/ml) for 24 hours. MMP13 mRNA levels were determined by qRT-PCR. Data represent the mean ± SD (n = 3) and are representative of 3 independent experiments. **P ≤ 0.01, by ANOVA. (E) MM cells were treated with IL-6 (20 ng/ml) for 24 hours, and MMP13 mRNA levels were determined by qRT-PCR. Data represent the mean ± SD (n = 3) and are representative of 3 independent experiments. **P ≤ 0.01, by 2-tailed Student’s t test. (F) RPMI 8266 cells were treated with IL-6 (20 ng/ml) for the indicated durations, and MMP-13 protein levels were analyzed in culture supernatants (SN) by Western blotting. Data are representative of 2 independent experiments.