Journal Article

Multiple myeloma–derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

Robinson, Samuel, Wang, Ji, Roodman, G. David, Normolle, Daniel, Lentzsch, Suzanne, Sabeh, Farideh, Weiss, Stephen J., Feng, Rentian, Mapara, Markus Y., Guo, X. Edward, Ma, Huihui, Lund, Thomas, Fu, Jing, Li, Shirong

2016

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Biomedical research / Bone diseases / Care and treatment / Cell Fusion / Complications and side effects / Enzymes / Female / Health aspects / Heterografts / Humans / Male / Matrix Metalloproteinase 13 - genetics / Matrix Metalloproteinase 13 - metabolism / Mice / Mice, Knockout / Multiple myeloma / Multiple Myeloma - enzymology / Multiple Myeloma - genetics / Multiple Myeloma - pathology / Multiple Myeloma - therapy / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Neoplasm Transplantation / Osteoclasts - enzymology / Osteoclasts - pathology / Osteolysis - enzymology / Osteolysis - genetics / Osteolysis - pathology / Osteolysis - therapy / Phosphatase / Physiological aspects / Studies