title: 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.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.forename: Shirong
authors.initials: S
authors.lastname: Li
authors.forename: Rentian
authors.initials: R
authors.lastname: Feng
authors.forename: Huihui
authors.initials: H
authors.lastname: Ma
authors.forename: Farideh
authors.initials: F
authors.lastname: Sabeh
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.forename: Samuel
authors.initials: S
authors.lastname: Robinson
authors.forename: X Edward
authors.initials: XE
authors.lastname: Guo
authors.forename: Thomas
authors.initials: T
authors.lastname: Lund
authors.forename: Daniel
authors.initials: D
authors.lastname: Normolle
authors.forename: Markus Y
authors.initials: MY
authors.lastname: Mapara
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
mesh_terms: D000818:Animals; D002459:Cell Fusion; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000201:enzymology* / Q000473:pathology; D010014:Osteolysis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy
chemical_list: D009363:Neoplasm Proteins; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13