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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report on an in vivo model of human myeloma producing bone disease in irradiated severe combined immunodeficiency disease mice using the human myeloma cell line JJN-3 and its subline JJN-3 T1. The cell lines are not Epstein-Barr virus transformed and produce large amounts of hepatocyte growth factor (HGF). Mice had radiological signs of osteolysis and mild hypercalcemia. Xenografted cells were predominantly found in bone marrow and brown adipose tissue, but also in meninges and liver. Take was documented by histopathological examination, immunophenotyping of cultured bone marrow, and radiography. HGF was detected in serum and bone marrow plasma. Disease generally occurred within 45 days of intravenous inoculation and was signaled by paraparesis or signs of intracranial neoplasia. More than 90% of the mice had take of xenografts. The subline JJN-3 T1 gave more reproducible bone marrow take than the native cell line. Bone histomorphometric examination revealed a 99% reduction in osteoblast counts and a 33% reduction in osteoclast counts in areas of tumor growth. Bone formation rates were reduced by 53%. The results suggest that osteoblastopenia and reduced bone formation is of importance for the occurrence of osteolytic lesions in this model.
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PMID:Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. 993 80

We determined the effects of the potent bisphosphonate ibandronate in a murine model of human myeloma bone disease. In this model, bone lesions typical of the human disease develop in mice following inoculation of myeloma cells via the tail vein. Treatment with ibandronate (4 micrograms per mouse per day) significantly reduced the occurrence of osteolytic bone lesions in myeloma-bearing mice. However, ibandronate did not prevent the mice from developing hindlimb paralysis and did not produce a detectable effect on survival. There was no significant effect of ibandronate on total myeloma cell burden, as assessed by morphometric measurements of myeloma cells in the bone marrow, liver, and spleen, or by measurement of serum IgG2b levels. These results support clinical findings that bisphosphonates may be useful for the treatment of myeloma-associated bone destruction, but suggest that other therapies are also required to reduce tumor growth.
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PMID:Ibandronate reduces osteolytic lesions but not tumor burden in a murine model of myeloma bone disease. 1002 99

Recombinant human erythropoietin (rHuEpo) has been used successfully in the treatment of cancer-related anemia. Clinical observations with several patients with multiple-myeloma treated with rHuEpo has shown, in addition to the improved quality of life, a longer survival than expected, considering the poor prognostic features of these patients. Based on these observations, we evaluated the potential biological effects of rHuEpo on the course of tumor progression by using murine myeloma models (MOPC-315-IgAlambda(2) and 5T33 MM-IgG(2b)). Here we report that daily treatment of MOPC-315 tumor-bearing mice with rHuEpo for several weeks induced complete tumor regression in 30-60% of mice. All regressors that were rechallenged with tumor cells rejected tumor growth, and this resistance was tumor specific. The Epo-triggered therapeutic effect was shown to be attributed to a T cell-mediated mechanism. Serum Ig analysis indicated a reduction in MOPC-315 lambda light chain in regressor mice. Intradermal inoculation of 5T33 MM tumor cells followed by Epo treatment induced tumor regression in 60% of mice. The common clinical manifestation of myeloma bone disease in patients with multiple-myeloma was established in these myeloma models. Epo administration to these tumor-bearing mice markedly prolonged their survival and reduced mortality. Therefore, erythropoietin seems to act as an antitumor therapeutic agent in addition to its red blood cell-stimulating activity.
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PMID:Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. 1130 90

Interleukin-6 (IL-6) is a multifunctional cytokine which provides multiple signals on various tissues and cells. In addition, IL-6 is produced by some human renal carcinoma cell lines in vitro and is expressed in a majority of primary renal cell carcinoma (RCC). Serum IL-6 influence the response to immunotherapy. IL-6 appears as a target for rational drug design highly promising for development of new cancer therapies. IL-6 effects are mediated by Stat. Stat (Signal transducers and activators of transcription) signaling pathways represent novel molecular targets for therapeutic implications in metastatic renal cell carcinoma. Inhibitors of Stat signaling pathway will not only block tumor growth by inducing apoptosis, but may also increase the sensitivity of tumors to conventional treatment (immunotherapy). The processes involved in tumor associated angiogenesis should lead to compounds able to interfere with angiogenesis. Il-6 has been implicated in the osteoclastic bone resorption and hypercalcemia associated with metastatic RCC. Different agents were shown to be effective in treating lytic bone disease mediated by osteoclast activation: bisphosphonates and osteoprotegerin.
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PMID:[Interleukin-6 and bone metastasis of renal cancer: molecular bases and therapeutic implications]. 1140 May 11

Invasion of the mineralized matrix by endothelial cells and osteoclasts is a key event in endochondral bone formation. To examine the putative role of osteoclast activity in the angiogenic process, we used two in vivo models of suppressed bone resorption: mice treated with the bisphosphonate clodronate and in osteoclast-deficient, osteopetrotic mice. Angiogenesis was assessed in caudal vertebrae of these neonatal mice. This model enables us to study the interaction between osteoclasts and endothelial cells during endochondral bone formation. In control conditions, sinusoid-like structures were detected in the vicinity of tartrate resistance acid phosphatase positive (TRAcP+) osteoclasts. Treatment with clodronate completely abolished osteoclastic bone resorption, whereas angiogenesis remained unaffected. In line with these observations, in the osteopetrotic mouse mutants c-fos knockout mice and op/op mice, capillaries invaded the calcified cartilage in the absence of osteoclasts. In conclusion, our data strongly suggest that during endochondral bone formation, vascular invasion can occur in the absence of osteo(chondro)clastic resorption. In addition, bisphosphonates show no apparent effect on angiogenesis in this in vivo model. These findings may have important clinical implications in the management of skeletal disorders such as metastatic bone disease, in which both osteoclastic bone resorption and angiogenesis contribute to tumor growth. On the other hand, our results confirm that bisphosphonates can be used safely in the treatment of disorders that affect the growing skeleton, such as in juvenile osteoporosis.
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PMID:Dissociation of angiogenesis and osteoclastogenesis during endochondral bone formation in neonatal mice. 1205 76

The aim of the present study was to determine whether modifying the local bone environment with osteoprotegerin (OPG), the soluble decoy receptor for receptor activator of nuclear factor-kappaB (RANK) ligand, could affect tumor burden and survival in the 5T33MM murine model of multiple myeloma. Treatment of mice, injected with 5T33MM cells, with recombinant OPG (Fc-OPG) caused a significant decrease in serum paraprotein and tumor burden and a significant increase in time to morbidity. This was associated with a decrease in osteoclast number in vivo but had no effect on apoptosis and proliferation of 5T33MM cells in vitro. These data indicate that targeting the bone microenvironment by inhibiting the interaction between RANK ligand and RANK with Fc-OPG not only inhibits the development of myeloma bone disease but also decreases tumor growth and increases survival.
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PMID:Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma. 1254 75

Small cell lung cancer (SCLC) is one of the most aggressive types of cancers because of its early development of regional and distant metastases. Novel and more effective therapeutic strategies for the treatment of this disease are necessary. Bisphosphonates (BP), originally developed to treat bone disease, have recently been identified as attractive cancer theraptic agents. In this study, we investigated the anti-proliferative effects of zoledronic acid (ZOL) as a single agent and in combination with other agents. ZOL inhibited both farnesylation and geranylgeranylation of RAS related proteins, induced apoptosis and inhibited the growth of eight out of twelve SCLC cell lines examined the in vitro. ZOL also significantly inhibited SCLC tumor growth and SBC-3 cells transplanted subcutaneously into nude mice. Its suppressive effect have not been completed, the addition effect of ZOL with other agents was examined. ZOL augmented the effects of paclitaxel, etoposide, cisplatinum and irinotecan synergistically, and imatinib mesylate additively. These findings indicate that ZOL and combined use of these agents may be promising therapeutic strategies for SCLC.
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PMID:Efficacy of the third-generation bisphosphonate, zoledronic acid alone and combined with anti-cancer agents against small cell lung cancer cell lines. 1611 74

Octreotide is one of the somatostatin analogue used for the treatment of endocrine tumors principally to suppress hormone secretion and to inhibit tumor growth. We experienced a case with multiple endocrine neoplasia type 1 who small amount of octreotide dramatically relieved the lumber pain caused by metastatic bone tumor. He had recurrent bronchial carcinoid tumors that metastasized to liver and bones. The spontaneous and radiated pain by bone tumors subsided within a few minutes after the initial injection of octreotide and the effect persisted for several hours. Combination therapy of octreotide and interferon alpha-2b significantly reduced the size of metastatic liver tumors and inhibited further growth of metastatic bone tumors for the last 27 months. The use of octreotide may be a good option for controlling pain by metastatic bone disease and combination therapy of octreotide and interferon alpha-2b is worth to try for patients with inoperable metastatic carcinoid tumor.
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PMID:Octreotide as a rapid and effective painkiller for metastatic carcinoid tumor. 1586 61

Bone destruction is a hallmark of multiple myeloma, and recent studies demonstrated a strong interdependence between tumor progression and bone resorption. Increased bone resorption as a major characteristic of multiple myeloma is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin (OPG) expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta and SDF-1alpha, which also increase osteoclast activity. Furthermore, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g. Dickkopf (DKK)-1. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression. Preclinical studies provided strong evidence that the suppression of the osteoclast activity using bisphosphonates, RANKL blockade or inhibition of MIP-1alpha or MIP-1beta is effective both in reducing myeloma bone disease and tumor growth and therefore may offer an important treatment strategy in multiple myeloma.
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PMID:Myeloma bone disease. 1618 25

Dickkopf-1 (DKK1), a soluble inhibitor of Wnt signaling secreted by multiple myeloma (MM) cells contributes to osteolytic bone disease by inhibiting the differentiation of osteoblasts. In this study, we tested the effect of anti-DKK1 therapy on bone metabolism and tumor growth in a SCID-rab system. SCID-rab mice were engrafted with primary MM cells expressing varying levels of DKK1 from 11 patients and treated with control and DKK1-neutralizing antibodies for 4 to 6 weeks. Whereas bone mineral density (BMD) of the implanted myelomatous bone in control mice was reduced during the experimental period, the BMD in mice treated with anti-DKK1 increased from pretreatment levels (P < .001). Histologic examination revealed that myelomatous bones of anti-DKK1-treated mice had increased numbers of osteocalcin-expressing osteoblasts and reduced number of multinucleated TRAP-expressing osteoclasts. The bone anabolic effect of anti-DKK1 was associated with reduced MM burden (P < .04). Anti-DKK1 also significantly increased BMD of the implanted bone and murine femur in nonmyelomatous SCID-rab mice, suggesting that DKK1 is physiologically an important regulator of bone remodeling in adults. We conclude that DKK1 is a key player in MM bone disease and that blocking DKK1 activity in myelomatous bones reduces osteolytic bone resorption, increases bone formation, and helps control MM growth.
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PMID:Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. 1706 50


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