{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T10:44:32Z","timestamp":1789209872225,"version":"build-2803163510"},"reference-count":60,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2007,9,10]],"date-time":"2007-09-10T00:00:00Z","timestamp":1189382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2008,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Matrix metalloproteinases (MMPs) are proteolytic enzymes that play critical roles in the pathogenesis of human cancers. Clinical trials using synthetic small molecule MMP inhibitors have been carried out but with little success. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that block the extracellular matrix\u2010degrading activity of MMPs. Here, we investigated the possibilities of genetically modifying human bones with TIMPs to create a high\u2010TIMP bone microenvironment, which is hostile to metastatic prostate cancer cells using adenovirus\u2010mediated gene transfer technology and SCID\u2010hu end\u2010organ colonization mouse model. Two strategies were used to achieve bone\u2010specific TIMP expression: (<jats:italic>i<\/jats:italic>) <jats:italic>ex vivo<\/jats:italic> bone adenoviral infection followed by <jats:italic>in vivo<\/jats:italic> bone implantation; and (<jats:italic>ii<\/jats:italic>) <jats:italic>ex vivo<\/jats:italic> BMS cell infection followed by injection into <jats:italic>in vivo<\/jats:italic> implanted human fetal bones. PC\u20103 prostate cancer cells were injected into human fetal bones 4 weeks after implantation in SCID mice. <jats:italic>In vitro<\/jats:italic>, adenovirus\u2010mediated expression of TIMP\u20101 or TIMP\u20102 in bone fragments inhibited MMP\u20102 activity, bone turnover and prostate cancer cell\u2010induced proteolytic degradation as determined by gelatin zymography, calcium measurement and DQ protein quenched fluorescence assay, respectively. <jats:italic>In vivo<\/jats:italic>, immunohistochemistry confirmed TIMP\u20102 expression in AdTIMP\u20102\u2010infected bone implants 4 weeks after implantation in SCID mice. Mice receiving AdTIMP\u2010treated bone fragments showed significantly reduced PC\u20103\u2010induced osteolysis, osteoclast recruitment and bone turnover in the implanted bones. We propose that adenoviral gene transfer of TIMP\u20101 and TIMP\u20102 can prevent the proteolytic activity of prostate cancer cells in bone and that enhancing anti\u2010proteolytic defense mechanisms in target organs represents a promising form of prostate cancer gene therapy. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.23053","type":"journal-article","created":{"date-parts":[[2007,9,10]],"date-time":"2007-09-10T15:46:30Z","timestamp":1189439190000},"page":"209-218","source":"Crossref","is-referenced-by-count":29,"title":["Adenovirus\u2010mediated expression of TIMP\u20101 and TIMP\u20102 in bone inhibits osteolytic degradation by human prostate 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