Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.
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PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and is attributable to osteoclast activation. Recent studies showed that the receptor activator of nuclear factor kappaB ligand (RANKL) is the key mediator of osteoclastogenesis and plays a crucial role in bone destruction in malignant bone disease. We found that human myeloma cells express RANKL and analyzed the association of the RANKL expression with the presence of osteolytic bone disease in patients with multiple myeloma. EXPERIMENTAL DESIGN: Flow cytometry was performed on bone marrow samples derived from controls and multiple myeloma patients with or without osteolytic bone lesions on conventional radiography. Plasma cells were identified as CD38++/CD138+ cells. The level of RANKL expression on the surface of bone marrow plasma cells was correlated with the bone status of the patients. RESULTS: The bone marrow plasma cells from controls showed no or only a weak surface expression of RANKL, and the median mean fluorescence index (MFI) was 6. In contrast, expression of RANKL could be detected on bone marrow plasma cells from all of the patients with multiple myeloma, and median MFI was 47. The difference in MFI for RANKL expression of bone marrow plasma cells from controls and myeloma patients was highly significant (P < 0.0005). Myeloma patients with osteolytic bone lesions showed a significantly higher expression of RANKL (median MFI = 60; range, 16-2494) compared with patients without osteolysis (median MFI = 16; range, 6-229; P < 0.0005). CONCLUSIONS: These results show for the first time that the level of RANKL expression by myeloma cells correlates significantly with osteolytic bone disease. (+info)
External auditory canal cholesteatoma: clinical and imaging spectrum.
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BACKGROUND AND PURPOSE: Cholesteatoma is an inflammatory lesion of the temporal bone that uncommonly involves the external auditory canal (EAC). In this large case series, we aimed to define its imaging features and to determine the characteristics most important to its clinical management. METHODS: Thirteen cases of EAC cholesteatoma (EACC) were retrospectively reviewed. Clinical data were reviewed for the history, presentation, and physical examination findings. High-resolution temporal bone CT scans were examined for a soft-tissue mass in the EAC, erosion of adjacent bone, and bone fragments in the mass. The middle ear cavity, mastoid, facial nerve canal, and tegmen tympani were evaluated for involvement. RESULTS: Patients presented with otorrhea, otalgia, or hearing loss. Eight cases were spontaneous, and five were postsurgical or post-traumatic. CT imaging in all 13 cases showed a soft-tissue mass with adjacent bone erosion. Intramural bone fragments were identified in seven cases. This mass most often arose inferiorly (n = 8) or posteriorly (n = 8), but it was circumferential in two cases. We noted middle ear extension (n = 5), mastoid involvement (n = 4), facial canal erosion (n = 2), and tegmen tympani dehiscence (n = 1). CONCLUSION: Temporal bone CT shows EACC as a soft-tissue mass within the EAC, with adjacent bone erosion. Bone fragments may be present within the mass. The cholesteatoma may extend into the mastoid or middle ear, or it may involve the facial nerve canal or tegmen tympani. Recognition of this entity and its possible extension is important because it may influence clinical management. (+info)
Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis.
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Bone metastasis of breast cancer induces severe osteolysis with increased bone resorption. Osteoclast differentiation regulated by the receptor activator of NF-kappaB ligand (RANKL) in osteoblasts and matrix degradation induced by matrix metalloproteinases (MMPs) are thought to be involved in the process of bone resorption. When nude mice were inoculated with human breast cancer cells, MDA-MB-231(MDA-231), numerous osteoclasts resorbed bone and the degradation of the bone matrix markedly progressed in the femur and tibia with metastasis of the MDA-231 tumour. The expression of RANKL, MMP-13 and membrane-type 1-MMP mRNA was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, MDA-231 markedly induced bone resorption measured by calcium release from the calvaria, and the expression of RANKL, MMP-2 and MMP-13 was elevated in the calvaria after the coculture. The separation of MDA-231 from the calvaria using filter insert showed decreased bone resorption, suggesting that cell-to-cell interaction is essential for cancer-induced bone resorption. Adding MDA-231 cells to bone marrow cultures markedly induced osteoclast formation, and the expression of RANKL in osteoblasts was enhanced by contact with the cell surface of MDA-231 cells. These results indicate that RANKL-induced osteoclast formation and MMP-dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer. (+info)
Elucidation of the potential roles of matrix metalloproteinases in skeletal biology.
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Irreversible destruction of joint structures is a major feature of osteoarthritis and rheumatoid arthritis. Fibrillar collagens in bone, cartilage and other soft tissues are critical for optimal joint form and function. Several approaches can be used to ascertain the role of collagenases, matrix metalloproteinases, in proteolysis of joint collagens in arthritis. These approaches include identifying spontaneous genetic disorders of the enzymes and substrates in humans and animals, as well as engineering mutations in the genes that encode these proteins in mice. Insights gained from such studies can be used to design new therapies to interrupt these catabolic events. (+info)
New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects.
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Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and its use in reducing osteoporosis and cancer-induced osteolysis is increasing. Recent findings indicated that ZOL has a direct effect on cancer cells. In this study, the effect of ZOL was examined on the aggressive MDA-MB-231 breast cancer cell line. ZOL induces an important inhibition of cell invasion at low concentrations (1 microM). This is not explained by modifications of proteases involved in cell invasiveness (matrix metalloproteinases and urokinase-type plasminogen activator), but by a disorganisation of actin cytoskeleton due to RhoA inhibition related to its defective prenylation as it was reversed by geranylgeraniol (GGOH) and mimicked by the Rho selective inhibitor C3 exoenzyme. In addition, ZOL inhibits the chemotactic effect induced by stromal cell-derived factor 1(SDF-1), a chemokine greatly involved in cancer metastasis to bone. This effect is related to both reduction of cell motility induced by RhoA inhibition and to a decreased expression of CXCR-4, the SDF-1 receptor. Finally, ZOL reduces Cox-2 expression and, consequently, the secretion of prostaglandins E2 (PGE2) in a RhoA-independent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclast-mediated bone resorption. In summary, new insights in the mechanism of ZOL action on aggressive breast cancer cells are demonstrated and could explain its beneficial action in both the reduction of osteolysis and prevention of metastasis. (+info)
A role for LIM kinase in cancer invasion.
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In this study, we show that LIM kinase 1 (LIMK1), a critical regulator of actin dynamics, plays a regulatory role in tumor cell invasion. We found that the level and activity of endogenous LIMK1 is increased in invasive breast and prostate cancer cell lines in comparison with less invasive cells. Overexpression of LIMK1 in MCF-7 and in MDA-MB-231 human breast cancer cell lines increased their motility, whereas the specific ROCK and Rho inhibitors Y-27632 and C3, respectively, attenuated this effect. In addition, inhibition of LIMK1 activity in the MDA-MB-231 cells by expression of dominant-negative LIMK1 resulted in decreased motility and formation of osteolytic bone lesions in an animal model of tumor invasion. This study shows an important role for LIMK1 signaling in invasion of cancer, demonstrating its potential as a therapeutic molecular target to decrease metastasis. (+info)
Extradural myxopapillary ependymoma with sacral osteolysis--a case report.
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Extradural ependymomas arising from filum terminale externa in the sacrococcygeal region are very rare. Since 1937, out of 58 cases reported in English literature, only 13 cases of tumor located presacrally in the retrorectal space, have been reported. The authors report a 38 yrs old male with a primary ependymoma of the sacrococcygeal region causing extensive sacral destruction. (+info)
Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis.
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Emerging evidence indicates that tumor-associated proteolytic remodeling of bone matrix may underlie the capacity of tumor cells to colonize and survive in the bone microenvironment. Of particular importance, urokinase-type plasminogen activator (uPA) has been shown to correlate with human prostate cancer (PC) metastasis. The importance of this protease may be related to its ability to initiate a proteolytic cascade, leading to the activation of multiple proteases and growth factors. Previously, we showed that maspin, a serine protease inhibitor, specifically inhibits PC-associated uPA and PC cell invasion and motility in vitro. In this article, we showed that maspin-expressing transfectant cells derived from PC cell line DU145 were inhibited in in vitro extracellular matrix and collagen degradation assays. To test the effect of tumor-associated maspin on PC-induced bone matrix remodeling and tumor growth, we injected the maspin-transfected DU145 cells into human fetal bone fragments, which were previously implanted in immunodeficient mice. These studies showed that maspin expression decreased tumor growth, reduced osteolysis, and decreased angiogenesis. Furthermore, the maspin-expressing tumors contained significant fibrosis and collagen staining, and exhibited a more glandular organization. These data represent evidence that maspin inhibits PC-induced bone matrix remodeling and induces PC glandular redifferentiation. These results support our current working hypothesis that maspin exerts its tumor suppressive role, at least in part, by blocking the pericellular uPA system and suggest that maspin may offer an opportunity to improve therapeutic intervention of bone metastasis. (+info)