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

破骨细胞是在成骨细胞表达的核因子受体激活剂(RANKL)的作用下，从单核巨噬系细胞分化为骨吸收破骨细胞。多西紫杉醇(Taxotere^&lt；R&gt；)被广泛用于治疗多种癌症，包括乳腺癌、卵巢癌和口腔癌。采用小鼠培养系统，探讨多西紫杉醇对破骨细胞性骨吸收的影响。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)共同作用下，小鼠成骨细胞和骨髓细胞在6天内形成破骨细胞。当多西紫杉醇作用于共培养细胞时，多西紫杉醇可剂量依赖地抑制1，25(OH)_2D_3+PGE_2诱导的破骨细胞的形成，并在10℃时完全抑制破骨细胞的形成，而在共培养的前3天加入多西紫杉醇，对破骨细胞的形成仍有轻微的抑制作用。将RANKL的诱骗受体--骨保护素加入到共培养细胞中，使破骨细胞的形成完全被抑制。1，25(OH)_2D_3+PGE_2诱导的成骨细胞RANKL的表达即使在10℃时也不受多西紫杉醇的影响。相反，多西他赛在牙本质片上放置的破骨细胞的凹坑形成活性即使在10^~(-7)M时也不被抑制，但在10^~(-6)M或更高时被抑制。这些结果表明，多西紫杉醇通过两个不同的过程抑制骨吸收：在10M时抑制破骨细胞的形成，在10M或更高时抑制成熟的破骨细胞的功能。

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.