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 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.
Lynch
Conor C
CC
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Hikosaka
Atsuya
A
Acuff
Heath B
HB
Martin
Michelle D
MD
Kawai
Noriyasu
N
Singh
Rakesh K
RK
Vargo-Gogola
Tracy C
TC
Begtrup
Jennifer L
JL
Peterson
Todd E
TE
Fingleton
Barbara
B
Shirai
Tomoyuki
T
Matrisian
Lynn M
LM
Futakuchi
Mitsuru
M
D000135:Acid Phosphatase / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics; D011471:Prostatic Neoplasms / Q000150:complications / Q000378:metabolism*; D053245:RANK Ligand; D051381:Rats; D011916:Rats, Inbred F344; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D012886:Skull / Q000473:pathology; D000071681:Tartrate-Resistant Acid Phosphatase; D015854:Up-Regulation / Q000235:genetics
D000199:Actins; D002352:Carrier Proteins; D006023:Glycoproteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C506032:Tnfrsf11b protein, rat; C505689:Tnfsf11 protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D020783:Matrix Metalloproteinase 7