BACKGROUND: The @entity3 of @entity263 to bone is associated with a substantial increase in bone matrix turnover. Matrix metalloproteinases (MMPs) play roles in both normal bone remodeling and invasion and @entity3 of @entity263 . This study was designed to determine the role of MMP activity in @entity263 that has metastasized to bone. METHODS: Single @entity1 fetal bone fragments were implanted subcutaneously in immunodeficient @entity19 . Four weeks later, @entity5049 @entity1 @entity263 cells were injected directly into some of the implants, and daily treatment was begun with batimastat (a broad-spectrum MMP inhibitor). There were six @entity19 (i.e., six implants) in each of four experimental arms: bone alone with and without batimastat and bone injected with @entity5049 cells with and without batimastat. Bone implants were harvested after 14 days of treatment and analyzed for MMP expression, bone histomorphometry, osteoclast counts, blood vessel density, and @entity5 cell proliferation and apoptosis. Complementary data were obtained from bone biopsy samples from @entity1 and a bone organ coculture system. All statistical tests were two-sided. RESULTS: MMPs were detected in @entity5 and stromal cells of clinical specimens and experimental bone implants. In vivo, MMP inhibition reduced the number of osteoclasts per millimeter in @entity5049 -injected implants-from 8.2 (95% confidence interval [CI] = 7.9 to 8.5) to 3.0 (95% CI = 2.3 to 3.7) (P =.006). In addition, it prevented degradation of marrow trabeculae within the bone implants (cross-sectional area of implant occupied by mineralized trabeculae: untreated implant = 29.1% [95% CI = 27.1% to 31.1%], @entity5049 -injected implant = 14.0% [95% CI = 10.9% to 17.1%] [P =.005 versus untreated], and batimastat-treated @entity5049 -injected implant = 27.2% [95% CI = 22.4% to 32.0%] [P =.03 versus @entity5049 injected alone]). MMP inhibition reduced proliferating @entity5 cells from 20.8% (95% CI = 19.9% to 21.7%) to 7.4% (95% CI = 5.2% to 9.6%) (P =.006), without affecting angiogenesis or apoptosis. In vitro, MMP inhibition had no toxic effect on @entity5049 cells but prevented calcium release from bone fragments cocultured with @entity5049 cells. CONCLUSIONS: MMP activity appears to play an important role in bone matrix turnover when @entity263 cells are present in bone. Bone matrix turnover and metastatic @entity5 growth appear to be involved in a mutually supportive cycle that is disrupted by MMP inhibition.

Matrix metalloproteinase activity, bone matrix turnover, and @entity5 cell proliferation in XXXX bone @entity3 .

@entity1 :: ('9606', 'Species') :: ['human', 'patients'] @entity263 :: ('MESH:D011471', 'Disease') :: ['prostate cancer'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor'] @entity3 :: ('MESH:D009362', 'Disease') :: ['metastasis'] @entity5049 :: ('57332', 'Gene') :: ['PC3']
@entity263 :: (MESH:D011471,Disease) :: ['prostate cancer']
