Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acid Phosphatase / metabolism
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Actins / metabolism
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Carrier Proteins / pharmacology
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Disease Models, Animal
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Down-Regulation / genetics
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Gene Expression / genetics
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Gene Expression Profiling
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Glycoproteins / genetics
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Humans
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Isoenzymes / metabolism
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Male
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Matrix Metalloproteinase 7 / genetics
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Matrix Metalloproteinase 7 / metabolism*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Biological
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Monocytes / drug effects
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Monocytes / metabolism
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Osteoclasts / metabolism
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Osteoclasts / pathology
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Osteolysis / etiology
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Osteolysis / metabolism
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Osteolysis / pathology*
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Osteoprotegerin
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Parathyroid Hormone-Related Protein / genetics
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Prostatic Neoplasms / complications
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Prostatic Neoplasms / metabolism*
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RANK Ligand
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Rats
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Rats, Inbred F344
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Tumor Necrosis Factor / genetics
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Skull / pathology
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Tartrate-Resistant Acid Phosphatase
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Up-Regulation / genetics
Substances
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Actins
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Carrier Proteins
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Glycoproteins
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Isoenzymes
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Membrane Glycoproteins
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Osteoprotegerin
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Parathyroid Hormone-Related Protein
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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TNFRSF11A protein, human
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TNFRSF11B protein, human
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TNFSF11 protein, human
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfrsf11b protein, rat
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Tnfsf11 protein, mouse
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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase
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Matrix Metalloproteinase 7