Involvement of Cyclo-Oxygenase-2 in Osteoclast Formation and Bone Destruction in Bone Metastasis of Mammary Carcinoma Cell Lines

Ono, Kohei; Akatsu, Takuhiko; Murakami, Takehiko; Kitamura, Reiko; Yamamoto, Michiko; Shinomiya, Nariyoshi; Rokutanda, Makoto; Sasaki, Taro; Amizuka, Norio; Ozawa, Hiroki; Nagata, Noriko; Kugai, Nobuo

doi:10.1359/jbmr.2002.17.5.774

Cited by 56 publications

(52 citation statements)

References 32 publications

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“…We observed that PTH induction of c-Fos, Pghs2 and Il6, genes involved in osteoclast formation and signaling (33)(34)(35)(36)(37), was slightly decreased in KO compared to WT cultures (data not shown). Thus, these preliminary observations suggest that CREM deficiency may affect the nature of the intermittent PTH response by modulating genes involved in osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 93%

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

Liu

Lee

Adams

et al. 2007

Bone

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CREM belongs to the ATF/CREB family of basic leucine zipper transcription factors. We previously showed that PTH induces ICER (inducible cAMP early repressor) in osteoblasts. ICER proteins, which are transcribed from the P2 promoter of the CREM gene, act as transcriptional attenuators. The objective of this study was to determine whether the Crem gene plays a role in the response of bone to intermittent PTH. Adult Crem knockout (KO) and wild type (WT) male mice were given daily subcutaneous injections of vehicle or hPTH(1-34) (160 μg/kg) for 10 days. Bone mineral content and density (BMC and BMD, respectively) were measured in femur and tibia by dual energy X-ray absorptiometry (DEXA). Bone morphometry was analyzed by X-ray computed microtomography (microCT) and histomorphometry. Serum bone turnover markers were measured. In vitro osteoclast formation assays were performed in bone marrow cultures treated with PTH or the combination of RANKL and M-CSF. KO mice had slightly higher basal bone mass than wild type mice. PTH treatment increased tibial BMC and BMD to a greater extent in WT mice compared to KO mice. PTH increased both cortical area and trabecular bone area in WT but not in KO femurs. PTH increased the bone formation rate and percent osteoblast surface to the same extent in femurs of WT and KO mice but increased osteoclast parameters and calvarial porosity to a greater extent in KO mice. PTH increased serum osteocalcin levels to the same extent in WT and KO mice. PTHinduced osteoclast formation was 2-fold greater in bone marrow cultures from KO mice. Collectively, our data suggest that the Crem deficiency in mice alters the response of bone to intermittent PTH treatment such that osteoclastogenesis is increased. Crem gene may specify the anabolic response to intermittent PTH treatment by restraining PTH-induced osteoclastogenesis.

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Section: Discussionmentioning

confidence: 93%

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

Liu

Lee

Adams

et al. 2007

Bone

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“…Invasive breast cancers, which constitutively express inducible Cox-2, enhance osteoclast formation through the production of high levels of PGE2 and subsequently an increase of osteolysis (Ono et al, 2002). As an important mechanism involved in the effect of BPs in bone marrow metastasis is the reduction of osteoclast-induced bone osteolysis, we also analysed whether ZOL could inhibit osteoclast activation by cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…One mechanism that contributes to osteoclast activation and metastasis-induced osteolysis is the release of PGE2 by cancer cells (Ono et al, 2002). Therefore, we evaluated the action of ZOL on Cox-2 mRNA and protein expression in MDA-MB-231 cells.…”

Section: Inhibition Of Cox-2 Expression and Pge2 Release By Zol On MDmentioning

confidence: 99%

“…It was demonstrated that invasive mammary cell lines, which constitutively express inducible Cox-2, enhance osteoclast formation through the production of high levels of prostaglandins E2 (PGE2) and subsequently induce an increase of osteolysis (Ono et al, 2002). We thus examined whether ZOL could affect the constitutive expression of Cox-2 in MDA-MB-231 cells.…”

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confidence: 99%

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New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Denoyelle¹,

Li²,

Jp³

et al. 2003

Br J Cancer

147

110

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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 mM). 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 RhoAindependent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclastmediated 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.

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“…IL-6 is a potent stimulator of osteoclast formation and can enhance the effects of PTHrP on osteoclasts [19,20]. Breast cancer cells also produce IL-1, TNF and prostaglandins which increase RANKL expression and stimulate osteoclasts [21,22]. A recent study showed that breast cancer cells could stimulate survival of osteoclastogenesis and prolong osteoclast survival by expressing and secreting CSF-1 [23,24].…”

Section: Osteolytic Metastasismentioning

confidence: 99%

Mechanisms of cancer metastasis to the bone

Yin¹,

Pollock²,

Kelly³

2005

Cell Res

307

226

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Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. This review discusses our current understanding of the molecular components and mechanisms that are responsible for those interactions.

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Involvement of Cyclo-Oxygenase-2 in Osteoclast Formation and Bone Destruction in Bone Metastasis of Mammary Carcinoma Cell Lines

Cited by 56 publications

References 32 publications

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Mechanisms of cancer metastasis to the bone

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