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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

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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.

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 2

MMP-13 mediates MM-induced OCL fusion and bone resorption.

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MMP-13 mediates MM-induced OCL fusion and bone resorption.
(A) Mouse non...
(A) Mouse nonadherent BM cells were cocultured with 5TGM1-EV or 5TGM1–MMP-13–KD #1 cells in Transwell dishes with M-CSF (10 ng/ml) and RANKL (50 ng/ml) for 4 days, with pro–MMP-13 added as indicated. OCLs were stained for TRAP and images captured as described in Methods. Scale bars: 100 μm. Data are representative of 3 independent experiments. CT, control. (B) Mouse OCL size (left panel), number of nuclei per OCL (middle panel), and number of OCLs per field (right panel) were assessed by microscopy and ImageJ software (NIH). Data represent the mean ± SEM (n = 3). *P ≤ 0.05 and **P ≤ 0.01, by ANOVA. (C) Mouse nonadherent BM cells were cultured with the indicated concentrations of pro–MMP-13 or vehicle during OCL formation in the presence of M-CSF (10 ng/ml) and RANKL (50 ng/ml). TRAP+ OCLs were scored microscopically. Scale bars: 100 μm. Data are representative of 4 independent experiments. (D) Mouse OCL size (left panel), number of nuclei per OCL (middle panel), and number of OCLs per field (right panel) were determined as above. Data represent the mean ± SEM (n = 3). P ≤ 0.0001, by linear regression (left panel) and Poisson regression (middle panel); P > 0.05 by Poisson regression (right panel). (E) Human mononuclear BM cells were cultured with the indicated concentrations of MMP-13 or vehicle during OCL formation in the presence of M-CSF (10 ng/ml) and RANKL (50 ng/ml). OCL numbers were determined by CD51/CD61 staining with 23c6 Ab and scored microscopically. Scale bars: 100 μm. Data are representative of 3 independent experiments. (F) Human OCL size, number of nuclei per OCL, and number of OCLs per well (right panel) were determined as above. Data represent the mean ± SEM (n = 3). P ≤ 0.0001, by linear regression (left panel) and Poisson regression (middle panel); P > 0.05 by Poisson regression (right panel).

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