MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL

We developed a rodent model that mimics the osteoblastic and osteolytic changes associated with human metastatic prostate cancer. Microarray analysis identified MMP-7, cathepsin-K, and apolipoprotein D as being upregulated at the tumor-bone interface. MMP-7, which was produced by osteoclasts at the...

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Bibliographic Details
Published in:Cancer cell 2005-05, Vol.7 (5), p.485-496
Main Authors: Lynch, Conor C., Hikosaka, Atsuya, Acuff, Heath B., Martin, Michelle D., Kawai, Noriyasu, Singh, Rakesh K., Vargo-Gogola, Tracy C., Begtrup, Jennifer L., Peterson, Todd E., Fingleton, Barbara, Shirai, Tomoyuki, Matrisian, Lynn M., Futakuchi, Mitsuru
Format: Article
Language:English
Subjects:
Acid Phosphatase - metabolism
Actins - metabolism
Animals
Carrier Proteins - genetics
Carrier Proteins - metabolism
Carrier Proteins - pharmacology
Disease Models, Animal
Down-Regulation - genetics
Gene Expression - genetics
Gene Expression Profiling
Glycoproteins - genetics
Humans
Isoenzymes - metabolism
Male
Matrix Metalloproteinase 7 - genetics
Matrix Metalloproteinase 7 - metabolism
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Membrane Glycoproteins - pharmacology
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Monocytes - drug effects
Monocytes - metabolism
Osteoclasts - metabolism
Osteoclasts - pathology
Osteolysis - etiology
Osteolysis - metabolism
Osteolysis - pathology
Osteoprotegerin
Parathyroid Hormone-Related Protein - genetics
Prostatic Neoplasms - complications
Prostatic Neoplasms - metabolism
RANK Ligand
Rats
Rats, Inbred F344
Receptor Activator of Nuclear Factor-kappa B
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Tumor Necrosis Factor - genetics
Skull - pathology
Tartrate-Resistant Acid Phosphatase
Up-Regulation - genetics
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Description
Summary:We developed a rodent model that mimics the osteoblastic and osteolytic changes associated with human metastatic prostate cancer. Microarray analysis identified MMP-7, cathepsin-K, and apolipoprotein D as being upregulated at the tumor-bone interface. MMP-7, which was produced by osteoclasts at the tumor-bone interface, was capable of processing RANKL to a soluble form that promoted osteoclast activation. MMP-7-deficient mice demonstrated reduced prostate tumor-induced osteolysis and RANKL processing. This study suggests that inhibition of MMP-7 will have therapeutic benefit in the treatment of prostate cancer-induced osteolysis.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2005.04.013