Takahashi Masahiro, Mizoguchi Toshihide, Uehara Shunsuke, Nakamichi Yuko, Yang Shuhua, Naramoto Hiroko, Yamashita Teruhito, Kobayashi Yasuhiro, Yamaoka Minoru, Furusawa Kiyofumi, Udagawa Nobuyuki, Uematsu Takashi, Takahashi Naoyuki
Department of Oral Maxillofacial Surgery, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan.
J Bone Miner Metab. 2009;27(1):24-35. doi: 10.1007/s00774-008-0013-y. Epub 2008 Dec 13.
Osteoclasts are formed from the monocyte-macrophage lineage in response to receptor activator of nuclear factor kappaB 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 D(3) plus prostaglandin E(2). 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 D(3) plus prostaglandin E(2) 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.
破骨细胞由单核细胞-巨噬细胞谱系形成，以响应成骨细胞表达的核因子κB受体活化因子配体（RANKL）。骨是乳腺癌转移最常见的部位，破骨细胞在转移过程中发挥作用。紫杉烷类化合物紫杉醇和多西他赛用于治疗包括乳腺癌在内的恶性疾病。在此，我们在小鼠培养系统中探究了多西他赛对破骨细胞骨吸收的影响。在用1,25-二羟基维生素D(3)加前列腺素E(2)处理的成骨细胞和骨髓细胞共培养物中，6天内即可形成破骨细胞。在整个培养期或前3天添加10(-8) M的多西他赛可抑制共培养物中破骨细胞的形成。即使在最后3天添加10(-6) M的多西他赛，也未能抑制破骨细胞的形成。骨保护素是RANKL的诱饵受体，在最后3天添加时可完全抑制破骨细胞的形成。10(-8) M的多西他赛可抑制成骨细胞和骨髓细胞的增殖。1,25-二羟基维生素D(3)加前列腺素E(2)诱导的成骨细胞中RANKL mRNA表达，即使在10(-6) M时也不受多西他赛的影响。10(-6) M而非10(-8) M的多西他赛可抑制在牙本质上培养的破骨细胞的陷窝形成活性。10(-6) M的多西他赛还可抑制破骨细胞的肌动蛋白环形成和L-谷氨酸分泌。因此，多西他赛以两种不同方式抑制骨吸收：10(-8) M时抑制破骨细胞形成，10(-6) M时抑制破骨细胞功能。这些结果表明紫杉烷类在骨转移性癌症治疗中具有有益作用。
