LC, a novel @entity1815 -rhein hybrid compound, concurrently stimulates @entity2159 and inhibits receptor activator of NF-kB ligand ( @entity5298 ) and @entity650 production by XXXX osteoblastic cells.

@entity172 @entity1 @entity650 @entity1782 @entity8047 @entity5 @entity604 @entity170 @entity3963 @entity5298 @entity1783 @entity10412 @entity1815 @entity35 @entity1299 @entity2159
@entity172 analogues are promising drugs for @entity170 , but because of their possible side effects such as increased risk of @entity5 , @entity172 which exert their estrogenic effects selectively on bone are desired. It has been shown that rhein inhibits osteoclast formation and bone resorption activity and has an antitumor role in several types of @entity5 . Having found that rhein had high affinity for the bone mineral, we synthesized @entity1815 -rhein hybrid compounds and confirmed that one of these hybrid compounds, LC, exhibited a selective profile in the bone and prevented @entity604 but had no effect on endometrium growth in ovariectomized @entity35 . However, the mechanisms underlying its actions on @entity1 bone cells have not been well defined. Here we show that LC concurrently stimulates @entity2159 ( @entity2159 ) and inhibits @entity5298 ( @entity5298 ) and @entity650 ( @entity650 ) production by @entity1 osteoblastic MG-63 cells containing two @entity172 receptor (ER) isotypes. Treatment with the ER antagonist @entity1299 abrogates the above actions of LC on osteoblast-derived cells. Using small interfering double-stranded RNAs (siRNA) technology, we further demonstrate that the effects of LC on @entity650 production are mediated by both @entity1782 and @entity1783 but those on @entity2159 and @entity5298 expression primarily by @entity1782 . Furthermore, we also demonstrate that LC functions at least partially through activation of the classic @entity172 response element (ERE) pathway as well as Ras/ @entity8047 / @entity3963 and @entity10412 /Akt signaling. The effect of LC on bone is due to not only its estrogenic activity but also action of its rhein moiety. Also, this compound shows much weaker effect on breast epithelial cell growth than that of @entity1815 . Therefore, using rhein for conjugating compounds is a promising method of effectively targeting @entity172 to the bone.
