Docetaxel inhibits bone resorption through suppression of osteoclast formation and fuction in different manners

多西紫杉醇通过不同方式抑制破骨细胞的形成和功能来抑制骨吸收

• 批准号: 18592208
• 负责人: TAKAHASHI Masahiro
• 金额: $ 2.36万
• 依托单位: Matsumoto Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18592208/
• 关键词: DOCETAXEL; BONE RESORPTION; OSTEOBLAST; OSTEOCLAST; MICROTUBULES

Bone-resorbing osteoclasts are differentiated from the monocyte-macrophage lineage cells in response to receptor activator of nuclear factor KB (RANKL) expressed by osteoblasts. Docetaxel (Taxotere^<R>) is widely used for the treatment for many kinds of cancers including breast, ovarian and oral cancers. Using mouse culture systems, we explored the effects of docetaxel on osteoclastic bone resorption. Osteoclasts were formed within 6 days in cocultures of mouse osteoblasts and bone marrow cells in the presence of 1, 25-dihydroxyvitamin D_3 [1, 25(OH)_2D_3] together with prostaglandin B_2 (PGE_2). When cocultures were treated with docetaxel for the entire culture period or for the first 3 days, docetaxel dose-dependently inhibited osteoclast formation induced by 1, 25(OH)_2D_3 plus PGE_2 with the complete inhibition at 10^<-8>M. However, docetaxel even at 10^<-6> added to the coculture for the fmal 3 days slightly inhibited the osteoclast formation. Osteoprotegerin, a decoy receptor of RANKL, added to the coculture for the entire culture period or the fmal 3 days completely inhibited osteoclast formation. Expression of RANKL induced by 1, 25(OH)_2D_3 plus PGE_2 in osteoblasts was not affected by docetaxel even at 10^<-6>M. Docetaxel at 10^<-8>M inhibited proliferation of osteoblasts and bone marrow cells. In contrast, the pit-forming activity of osteoclasts placed on dentine slices was not inhibited by docetaxel even at 10^<-7>M but inhibited at 10^<-6>M or more. These results suggest that docetaxel inhibits bone resorption in two different processes: inhibition of osteoclast formation at 10^<-8>M, and function of mature osteoclasts at 10^<-6>M or more.

骨吸收破骨细胞是在成骨细胞表达核因子KB受体激活因子（RANKL）的作用下从单核-巨噬细胞谱系细胞分化而来的。多西他赛（Taxotere）被广泛用于治疗多种癌症，包括乳腺癌、卵巢癌和口腔癌。利用小鼠培养系统，我们探讨了多西他赛对破骨细胞骨吸收的影响。小鼠成骨细胞与骨髓细胞在1,25 -二羟基维生素D_3 [1,25 (OH)_2D_3]和前列腺素B_2 （PGE_2）存在下共培养6 d内形成破骨细胞。多西他赛在全培养期和前3天对1,25 (OH)_2D_3 + PGE_2诱导的破骨细胞形成有剂量依赖性的抑制作用，在10^<-8>M时完全抑制。然而，即使在10^<-6>的浓度下加入共培养3天，多西他赛也能轻微抑制破骨细胞的形成。在共培养中加入RANKL的诱饵受体骨保护素（Osteoprotegerin），在整个培养周期或正式的3天内完全抑制破骨细胞的形成。1,25 (OH)_2D_3 + PGE_2诱导的RANKL在成骨细胞中的表达即使在10^<-6>M时多西他赛也不受影响。多西他赛在10^<-8>M时抑制成骨细胞和骨髓细胞的增殖。相比之下，即使在10^<-7>M时，多西他赛也没有抑制牙本质片上的破骨细胞的凹窝形成活性，但在10^<-6>M或更高时，破骨细胞的凹窝形成活性受到抑制。这些结果表明，多西他赛通过两个不同的过程抑制骨吸收：在10^<-8>M时抑制破骨细胞的形成，在10^<-6>M或更高时抑制成熟破骨细胞的功能。

项目成果

Refractory factors in head and neck cancer : ATP binding cassette transportors expressed in head and neck cancer cell lines.

头颈癌的难治因素：头颈癌细胞系中表达的 ATP 结合盒转运蛋白。

• 发表时间: 2006
• 期刊: Oral sci. int. 3(2)
• 作者: Uematsu T;他;Uematsu T
• 通讯作者: Uematsu T

Docetaxel inhibits bone resorption through supression of osteoclast formation and function in different manners.

多西紫杉醇通过以不同方式抑制破骨细胞的形成和功能来抑制骨吸收。

• 发表时间: 2008
• 期刊: JBMM. (in press)
• 作者: Yamaoka M.;他;Yamaoka M;Takahashi M
• 通讯作者: Takahashi M

Multidrug resistance-associated protein 7 expression is involved in cross-resistance to docetaxel in salivary gland adenocarcinoma cell lines.

• DOI: 10.3892/ijo.30.2.393
• 发表时间: 2007-02
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: Hiroko Naramoto;T. Uematsu;T. Uchihashi;R. Doto;T. Matsuura;Y. Usui;S. Uematsu;Xianqi Li;Masahiro Takahashi;M. Yamaoka;K. Furusawa

Effect of inorganic polyphoshate in periodontitis in the elderly.

无机多磷酸盐治疗老年人牙周炎的作用。

• 发表时间: 2008
• 期刊: Gerodontology.
• 作者: Yamaoka M.;他;Yamaoka M
• 通讯作者: Yamaoka M

Inorganic polyphosphate: a possible stimulant of bone formation

• DOI: 10.1177/154405910708600917
• 发表时间: 2007-09-01
• 期刊: JOURNAL OF DENTAL RESEARCH
• 影响因子: 7.6
• 作者: Hacchou, Y.;Uematsu, T.;Furusawa, K.
• 通讯作者: Furusawa, K.