title: Docetaxel inhibits bone resorption through suppression of osteoclast formation and function in different manners.
abstract: 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.
authors.affiliation: Department of Oral Maxillofacial Surgery, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takahashi
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mizoguchi
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Uehara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakamichi
authors.forename: Shuhua
authors.initials: S
authors.lastname: Yang
authors.forename: Hiroko
authors.initials: H
authors.lastname: Naramoto
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Minoru
authors.initials: M
authors.lastname: Yamaoka
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Furusawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Uematsu
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Takahashi
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D001862:Bone Resorption; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002117:Calcitriol / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000378:metabolism; D000077143:Docetaxel; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D053245:RANK Ligand; D043823:Taxoids; D000077143:Docetaxel; D018698:Glutamic Acid; D002117:Calcitriol; D015232:Dinoprostone; D017239:Paclitaxel