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101.
Masahiro Takahashi Toshihide Mizoguchi Shunsuke Uehara Yuko Nakamichi Shuhua Yang Hiroko Naramoto Teruhito Yamashita Yasuhiro Kobayashi Minoru Yamaoka Kiyofumi Furusawa Nobuyuki Udagawa Takashi Uematsu Naoyuki Takahashi 《Journal of bone and mineral metabolism》2009,27(1):24-35
Osteoclasts are formed from the monocyte-macrophage lineage in response to receptor activator of nuclear factor κB ligand
(RANKL) expressed by osteoblasts. Bone is the most common site of breast cancer metastasis, and osteoclasts play roles in
the metastasis. The taxane-derived compounds paclitaxel and docetaxel are used for the treatment of malignant diseases, including
breast cancer. Here we explored the effects of docetaxel on osteoclastic bone resorption in mouse culture systems. Osteoclasts
were formed within 6 days in cocultures of osteoblasts and bone marrow cells treated with 1,25-dihydroxyvitamin D3 plus prostaglandin E2. Docetaxel at 10−8 M inhibited osteoclast formation in the coculture when added for the entire culture period or for the first 3 days. Docetaxel,
even at 10−6 M added for the final 3 days, failed to inhibit osteoclast formation. Osteoprotegerin, a decoy receptor of RANKL, completely
inhibited osteoclast formation when added for the final 3 days. Docetaxel at 10−8 M inhibited the proliferation of osteoblasts and bone marrow cells. RANKL mRNA expression induced by 1,25-dihydroxyvitamin
D3 plus prostaglandin E2 in osteoblasts was not affected by docetaxel even at 10−6 M. Docetaxel at 10−6 M, but not at 10−8 M, inhibited pit-forming activity of osteoclasts cultured on dentine. Actin ring formation and l-glutamate secretion by osteoclasts were also inhibited by docetaxel at 10−6 M. Thus, docetaxel inhibits bone resorption in two different manners: inhibition of osteoclast formation at 10−8 M and of osteoclast function at 10−6 M. These results suggest that taxanes have beneficial effects in the treatment of bone metastatic cancers.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
102.
Kazushi Takayama Akinobu Suzuki Tomoya Manaka Susumu Taguchi Yusuke Hashimoto Yuuki Imai Shigeyuki Wakitani Kunio Takaoka 《Journal of bone and mineral metabolism》2009,27(4):402-411
Noggin is a major extracellular antagonist to bone morphogenetic proteins (BMPs) which binds to BMPs and blocks binding of
them to BMP-specific receptors and negatively regulates BMP-induced osteoblastic differentiation. In this study, we investigated
the effect of noggin silencing by transfection of small interfering RNA (siRNA) on BMP-induced osteoblastic differentiation
in vitro and ectopic bone formation in vivo induced by recombinant human BMP-2 (rhBMP-2). Noggin mRNA expression was up-regulated
in response to rhBMP-2 in C2C12 cells, a myoblastic cell line, in dose- and time-dependent fashion as determined by real-time
RT-PCR assay. Silencing of noggin expression by transfection of noggin siRNA suppressed BMP-stimulated noggin expression,
resulting in acceleration of BMP-induced osteoblastic differentiation. For in vivo noggin silencing, siRNA was injected locally
into back muscles and transfected into local cells by electroporation, where rhBMP-2-retaining (5 μg) collagen disks had been
surgically placed. The implants were harvested at 2 weeks after surgery from experimental and control group mice and analyzed
by radiological and histological methods. As a result, bone mineral content of ossicles ectopically induced by rhBMP-2 was
significantly increased by silencing of noggin. Our findings suggest that silencing of noggin enhances the osteoblastic differentiation
of BMP-responding cells in vitro and new bone formation induced by rhBMP-2 in vivo by eliminating negative regulation of the
effects of BMP. RNA interference might be useful for intensifying the effects of BMP in promoting new bone (callus) formation
in repair of damaged bone. 相似文献
103.
Nguyen Huu Tung Yan Ding Eun Mi Choi Phan Van Kiem Chau Van Minh Young Ho Kim 《Archives of pharmacal research》2009,32(4):515-520
Two new anthracene glycosides (1, 2) were isolated from aerial parts of Rhodomyrtus tomentosa, along with three known compounds (3–5). The structures of two new compounds were established to be 4,8,9,10-tetrahydroxy-2,3,7-trimethoxyanthracene-6-O-β-D-glucopyranoside (1) and 2,4,7,8,9,10-hexahydroxy-3-methoxyanthracene-6-O-α-L-rhamnopyranoside (2) based on spectroscopic and chemical methods. Among them, compound 1, 2, and 5 significantly (P<0.05) increased the alkaline phosphatase activity, collagen synthesis, and mineralization of the nodules of MC3T3-E1 osteoblastic
cells compared to those of the control, respectively. 相似文献
104.
人健康和炎性牙槽骨成骨细胞COX-2、PGE2、OPG,RANKL的表达 总被引:2,自引:1,他引:1
目的:初步探讨COX-2、PGE2、OPG和RANKL在牙周炎发病机制中所起的作用及其相互关系。方法:采用组织块法对人健康和牙周炎性牙槽骨进行体外培养和传代,加入含100μg/LrhOPG的不含胎牛血清的DMEM2mL。严格按照ELISA试剂盒说明进行操作,获得各指标的检测数值。结果:牙周炎组RANKL、PGE2、COX-2的表达较健康组明显增高,OPG的表达较健康组明显降低。加入rhOPG后,牙周炎组RANKL、PGE2、COX-2的表达明显降低;OPG表达明显增加。健康组RANKL、PGE2、COX-2表达明显降低;OPG表达增加。结论:RANKL、PGE2、COX-2可促进牙周炎的发生、发展,而OPG对牙周炎的发生、发展可起抑制作用,同时表明人工重组OPG可能协同其内源性OPG来共同抑制RANKL、PGE2、COX-2的活性。 相似文献
105.
Idris AI Rojas J Greig IR Van't Hof RJ Ralston SH 《Calcified tissue international》2008,82(3):191-201
Bisphosphonates are widely used for the treatment of bone diseases associated with increased osteoclastic bone resorption. Bisphosphonates are known to inhibit biochemical markers of bone formation in vivo, but it is unclear to what extent this is a consequence of osteoclast inhibition or a direct inhibitory effect on cells of the osteoblast lineage. In order to investigate this issue, we studied the effects of various bisphosphonates on osteoblast growth and differentiation in vitro. The aminobisphosphonates pamidronate and alendronate inhibited osteoblast growth, caused osteoblast apoptosis, and inhibited protein prenylation in osteoblasts in a dose-dependent manner over the concentration range 20-100 microM. Further studies showed that alendronate in a dose of 0.1 mg/kg inhibited protein prenylation in calvarial osteoblasts in vivo, indicating that alendronate can be taken up by osteoblasts in sufficient amounts to inhibit protein prenylation at clinically relevant doses. Pamidronate and alendronate inhibited bone nodule formation at concentrations 10-fold lower than those required to inhibit osteoblast growth. These effects were not observed with non-nitrogen-containing bisphosphonates or with other inhibitors of protein prenylation and were only partially reversed by cotreatment with a fourfold molar excess of ss-glycerol phosphate. We conclude that aminobisphosphonates cause osteoblast apoptosis in vitro at micromolar concentrations and inhibit osteoblast differentiation at nanomolar concentrations by mechanisms that are independent of effects on protein prenylation and may be due in part to inhibition of mineralization. While these results need to be interpreted with caution because of uncertainty about the concentrations of bisphosphonates that osteoblasts are exposed to in vivo, our studies clearly demonstrate that bisphosphonates exert strong inhibitory effects on cells of the osteoblast lineage at similar concentrations to those that cause osteoclast inhibition. This raises the possibility that inhibition of bone formation by bisphosphonates may be due in part to a direct inhibitory effect on cells of the osteoblast lineage. 相似文献
106.
Kimura M Miyazawa K Tabuchi M Maeda H Kameyama Y Goto S 《Calcified tissue international》2008,82(2):137-147
Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor receptor family which plays a crucial role in
negative regulation of osteoclastic bone resorption. OPG-deficient (OPG–/–) mice develop severe osteoporosis caused by significant
enhancement of bone resorption by osteoclasts. We investigated the effect of administering bisphosphonate on mandibular growth
and development in OPG–/– mice. Eight-week-old male OPG–/– mice and wild-type (WT) mice were administered bisphosphonate (1.25 mg/kg
body weight) intraperitoneally once every 3 days for 30 days. All bone formation-related parameters and bone resorption-related
parameters were significantly lower in OPG–/– mice with bisphosphonate than in those without bisphosphonate. The volume of
the whole condyle and the mandibular length in OPG–/– mice without bisphosphonate were significantly smaller than in WT mice
without bisphosphonate. Bisphosphonate treatment of the OPG–/– mice resulted in an increase in the volume of the mandibular
condyle and mandibular ramus length. In fact, the mandibular ramus length in OPG–/– mice with bisphosphonate was similar to
the length in WT mice without bisphosphonate. Histologically, the surface irregularity of the mandibular condyle that was
observed in the OPG–/– mice without bisphosphonate tended to be less marked in the OPG–/– mice with bisphosphonate, and the
proportion of the area of the cartilage layer relative to the whole condyle was significantly larger in OPG–/– mice with bisphosphonate
than in those without bisphosphonate. In conclusion, bisphosphonate treatment results in an increase in mandibular condylar
dimensions and normalization of mandibular ramus growth. 相似文献
107.
108.
Mechanical force-induced midpalatal suture remodeling in mice 总被引:3,自引:0,他引:3
Mechanical stress is an important epigenetic factor for regulating skeletal remodeling, and application of force can lead to remodeling of both bone and cartilage. Chondrocytes, osteoblasts and osteoclasts all participate and interact with each other in this remodeling process. To study cellular responses to mechanical stimuli in a system that can be genetically manipulated, we used mouse midpalatal suture expansion in vivo. Six-week-old male C57BL/6 mice were subjected to palatal suture expansion by opening loops with an initial force of 0.56 N for the periods of 1, 3, 5, 7, 14 or 28 days. Periosteal cells in expanding sutures showed increased proliferation, with Ki67-positive cells representing 1.8 ± 0.1% to 4.5 ± 0.4% of total suture cells in control groups and 12.0 ± 2.6% to 19.9 ± 1.2% in experimental/expansion groups (p < 0.05). Starting at day 1, cells expressing alkaline phosphatase and type I collagen were seen. New cartilage and bone formation was observed at the oral edges of the palatal bones at day 7; at the nasal edges only bone formation without cartilage appeared to occur. An increase in osteoclast numbers suggested increased bone remodeling, ranging from 60 to 160% throughout the experimental period. Decreased Saffranin O staining after day 3 suggested decreased proteoglycan content in the secondary cartilage. Micro-CT showed a significant increase in maxillary width at days 14 and 28 (from 2334 ± 4 μm to 2485 ± 3 μm at day 14 and from 2383 ± 5 μm to 2574 ± 7 μm at day 28, p < 0.001). The suture width was increased at days 14 and 28, except in the oral third region at day 28 (from 48 ± 5 μm to 36 ± 4 μm, p < 0.05). Bone volume/total volume was significantly reduced at days 14 and 28 (50.2 ± 0.7% vs. 68.0 ± 3.7% and 56.5 ± 1.0% vs. 60.9 ± 1.3%, respectively, p < 0.05), indicative of increased bone marrow space. These findings demonstrate that expansion forces across the midpalatal suture promote bone resorption through activation of osteoclasts and bone and cartilage formation via increased proliferation and differentiation of periosteal cells. Mouse midpalatal suture expansion would be useful in further studies of the ability of mineralized tissues to respond to mechanical stimulation. 相似文献
109.
目的: 探讨牙髓卟啉单胞菌(Porphyromonas endodontalis,P.endodontalis)脂多糖对小鼠成骨细胞表达单核细胞趋化蛋白1(monocyte chemotactic protein-1, MCP-1)mRNA和蛋白的影响,以及是否有p38丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路和核因子κB(Nuclear Factor-κB, NF-κB)信号通路的参与。方法: 以不同质量浓度的P.endodontalis脂多糖(0~50 mg/L)刺激MC3T3-E1细胞24 h;以20 mg/L P.endodontalis脂多糖作用于细胞不同时间(0~48 h)后,采用实时反转录PCR和酶联免疫吸附测定检测MCP-1mRNA和蛋白的表达。采用p38MAPK抑制剂SB203580和NF-κB抑制剂BAY11-7082分别预处理细胞1 h,检测其对P.endodontalis脂多糖刺激MC3T3-E1细胞后MCP-1mRNA表达的影响。采用SPSS 13.0软件包对结果进行单因素方差分析和Dunnett t检验。结果: 不同质量浓度的P.endodontalis脂多糖(0~50 mg/L)刺激MC3T3-E1细胞后,MCP-1的mRNA表达和蛋白分泌呈剂量依赖性;观察时间内(0~48 h),20 mg/L P.endodontalis脂多糖作用于MC3T3-E1细胞后,MCP-1 mRNA的表达和蛋白分泌呈时间依赖性;10 mol/L的SB203580和BAY11-7082分别预处理细胞1 h,可以降低P.endodontalis脂多糖诱导MCP-1 mRNA的表达,且SB203580的抑制作用强于BAY11-7082。结论: P.endodontalis脂多糖可能通过激活p38MAPK和NF-κB信号通路诱导成骨细胞表达MCP-1mRNA和蛋白。 相似文献
110.
J. P. T. M. van Leeuwen H. A. P. Pols J. P. Schilte T. J. Visser J. C. Birkenhäger 《Calcified tissue international》1991,49(1):35-42
Summary The effects of epidermal growth factor (EGF) on basal 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) receptor level and on parathyroid hormone (PTH)-induced 1,25-(OH)2D3 (OH)2D3 receptor up-regulation were studied in the phenotypically osteoblastic cell line UMR 106. EGF in concentrations exceeding
0.1 ng/ml reduced the number of 1,25(OH)2D3 binding sites without changing the binding affinity. Maximal reduction was 30% at about 1 ng/ml. This reduction was independent
of a change in cAMP content. EGF dose-dependently attenuated both PTH-induced 1,25(OH)2D3 receptor up-regulation and PTH-stimulated cAMP production without and effect on the ED50 of the PTH effects. For both PTH responses the IC50 and the maximal effective dose were similar, 0.1 ng/ml an 1 ng/ml EGF, respectively. Reduction was first seen at 0.01 ng/ml
EGF. At this concentration. EGF reduced PTH-stimulated 1,25-(OH)2D3 receptor binding without an inhibition of the cAMP response. Time-course studies with 1 ng/ml EGF revealed that at 2 h preincubation
EGF reduced the heterologous up regulation by PTH, and maximal inhibition was seen after 4 h. In contrast, PTH-stimulated
cAMP production was just significantly inhibited only after 6 h, with 60% inhibition after 24 h preincubation. The effects
of prostaglandin E2 and forskolin on both 1,25(OH)2D3 binding and cAMP production were inhibited in a similar fashion. On the other hand, dibutyryl cAMP- and 3-isobutyl-1-methylxanthinestimulated
1,25(OH)2D3 binding were not affected by EGF. Taken together, our results demonstrate that EGF reduces both the basal number of 1,25(OH)2D3 binding sites and the heterologous up-regulation of the 1,25(OH)2D3 receptor. The current data suggest that EGF reduces heterologous upregulation of the 1,25(OH)2D3 receptor independent of as well as dependent on the cAMP messenger system. The EGF effect is not primarily located at the
PTH receptor, at cAMP phosphodiesterase, or at protein kinase A level. 相似文献