title: A loss of host-derived MMP-7 promotes myeloma growth and osteolytic bone disease in vivo.
abstract: Matrix metalloproteinases (MMPs) play a critical role in cancer pathogenesis, including tumor growth and osteolysis within the bone marrow microenvironment. However, the anti-tumor effects of MMPs are poorly understood, yet have significant implications for the therapeutic potential of targeting MMPs. Host derived MMP-7 has previously been shown to support the growth of bone metastatic breast and prostate cancer. In contrast and underscoring the complexity of MMP biology, here we identified a tumor-suppressive role for host MMP-7 in the progression of multiple myeloma in vivo. An increase in tumor burden and osteolytic bone disease was observed in myeloma-bearing MMP-7 deficient mice, as compared to wild-type controls. We observed that systemic MMP-7 activity was reduced in tumor-bearing mice and, in patients with multiple myeloma this reduced activity was concomitant with increased levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Our studies have identified an unexpected tumour-suppressive role for host-derived MMP-7 in myeloma bone disease in vivo, and highlight the importance of elucidating the effect of individual MMPs in a disease-specific context.
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.|Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK.|Department of Medicine/Clinical Pharmacology, Vanderbilt Center for Bone Biology, Nashville, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Lwin
authors.affiliation: Department of Medicine/Clinical Pharmacology, Vanderbilt Center for Bone Biology, Nashville, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Fowler
authors.affiliation: Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Drake
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK.|Department of Medicine/Clinical Pharmacology, Vanderbilt Center for Bone Biology, Nashville, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Edwards
authors.affiliation: Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Lynch
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. claire.edwards@ndorms.ox.ac.uk.|Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK. claire.edwards@ndorms.ox.ac.uk.|Department of Medicine/Clinical Pharmacology, Vanderbilt Center for Bone Biology, Nashville, USA. claire.edwards@ndorms.ox.ac.uk.
authors.forename: C M
authors.initials: CM
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D055786:Gene Knockout Techniques; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009368:Neoplasm Transplantation; D059016:Tumor Microenvironment
chemical_list: C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7
keywords: Bone; Bone disease; MMP-7; Microenvironment; Mouse model; Multiple myeloma; Osteoclast