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Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro

Michael, H.; Härkönen, Pirkko LU ; Kangas, L.; Vaananen, H. K. and Hentunen, T. A. (2007) In British Journal of Pharmacology 151(3). p.384-395
Abstract
Background and purpose: Several selective oestrogen receptor modulators ( SERMs) with oestrogen agonist effects in bone cells and without increased risk of breast and endometrial cancer have been developed. Here, we have investigated the effects of different types of SERMs on osteoclast differentiation, bone resorption and apoptosis in vitro. Experimental approach: Human peripheral blood- derived CD14(+) monocytes were cultured on bovine bone slices in the presence of RANKL, M-CSF, TNF-alpha and dexamethasone for seven days. Also, CD14(+) monocytes were co- cultured either with human SaOS-2 or MG-63 osteosarcoma cells, in the presence of parathyroid hormone. Osteoclast cultures were treated with different SERMs. TRACP(+) multinucleated... (More)
Background and purpose: Several selective oestrogen receptor modulators ( SERMs) with oestrogen agonist effects in bone cells and without increased risk of breast and endometrial cancer have been developed. Here, we have investigated the effects of different types of SERMs on osteoclast differentiation, bone resorption and apoptosis in vitro. Experimental approach: Human peripheral blood- derived CD14(+) monocytes were cultured on bovine bone slices in the presence of RANKL, M-CSF, TNF-alpha and dexamethasone for seven days. Also, CD14(+) monocytes were co- cultured either with human SaOS-2 or MG-63 osteosarcoma cells, in the presence of parathyroid hormone. Osteoclast cultures were treated with different SERMs. TRACP(+) multinucleated cells and C- terminal telopeptide of type I collagen were used as markers for osteoclast formation and bone resorption, respectively. Key Results: In CD14(+) monocyte cultures, tamoxifen directly inhibited human osteoclast formation and bone resorption, while raloxifene and ospemifene had no inhibitory effect. In the co- cultures either with SaOS- 2 or MG- 63 cells, ospemifene and raloxifene as well as tamoxifen inhibited osteoclast formation in a concentration- dependent manner. The inhibitory effect was associated with an increased production of osteoprotegerin. The anti- oestrogen ICI 182 780 completely reversed the effects of these SERMs. Conclusion and Implications: Tamoxifen had an oestrogen receptor dependent, direct, inhibitory effect o on human osteoclast differentiation and bone resorption, whereas ospemifene and raloxifene required osteoblastic cells to achieve a similar inhibition. The effects of ospemifene and raloxifene were mediated by oestrogen receptors by a mechanism involving paracrine induction of osteoprotegerin in cultures with osteoblast derived osteosarcoma cells. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
bone, osteoclast differentiation, raloxifene, tamoxifen, ospemifene, osteoprotegerin, resorption
in
British Journal of Pharmacology
volume
151
issue
3
pages
384 - 395
publisher
The British Pharmacological Society
external identifiers
  • wos:000247173000010
  • scopus:34249690772
ISSN
1476-5381
DOI
10.1038/sj.bjp.0707232
language
English
LU publication?
yes
id
d9744126-ba5c-443a-8937-5504f0f29a3a (old id 648971)
date added to LUP
2007-12-14 09:16:08
date last changed
2017-10-01 04:46:10
@article{d9744126-ba5c-443a-8937-5504f0f29a3a,
  abstract     = {Background and purpose: Several selective oestrogen receptor modulators ( SERMs) with oestrogen agonist effects in bone cells and without increased risk of breast and endometrial cancer have been developed. Here, we have investigated the effects of different types of SERMs on osteoclast differentiation, bone resorption and apoptosis in vitro. Experimental approach: Human peripheral blood- derived CD14(+) monocytes were cultured on bovine bone slices in the presence of RANKL, M-CSF, TNF-alpha and dexamethasone for seven days. Also, CD14(+) monocytes were co- cultured either with human SaOS-2 or MG-63 osteosarcoma cells, in the presence of parathyroid hormone. Osteoclast cultures were treated with different SERMs. TRACP(+) multinucleated cells and C- terminal telopeptide of type I collagen were used as markers for osteoclast formation and bone resorption, respectively. Key Results: In CD14(+) monocyte cultures, tamoxifen directly inhibited human osteoclast formation and bone resorption, while raloxifene and ospemifene had no inhibitory effect. In the co- cultures either with SaOS- 2 or MG- 63 cells, ospemifene and raloxifene as well as tamoxifen inhibited osteoclast formation in a concentration- dependent manner. The inhibitory effect was associated with an increased production of osteoprotegerin. The anti- oestrogen ICI 182 780 completely reversed the effects of these SERMs. Conclusion and Implications: Tamoxifen had an oestrogen receptor dependent, direct, inhibitory effect o on human osteoclast differentiation and bone resorption, whereas ospemifene and raloxifene required osteoblastic cells to achieve a similar inhibition. The effects of ospemifene and raloxifene were mediated by oestrogen receptors by a mechanism involving paracrine induction of osteoprotegerin in cultures with osteoblast derived osteosarcoma cells.},
  author       = {Michael, H. and Härkönen, Pirkko and Kangas, L. and Vaananen, H. K. and Hentunen, T. A.},
  issn         = {1476-5381},
  keyword      = {bone,osteoclast differentiation,raloxifene,tamoxifen,ospemifene,osteoprotegerin,resorption},
  language     = {eng},
  number       = {3},
  pages        = {384--395},
  publisher    = {The British Pharmacological Society},
  series       = {British Journal of Pharmacology},
  title        = {Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro},
  url          = {http://dx.doi.org/10.1038/sj.bjp.0707232},
  volume       = {151},
  year         = {2007},
}