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

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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; Kangas, L.; Vaananen, H. K.; Hentunen, T. A.

I: British Journal of Pharmacology, Vol. 151, Nr. 3, 2007, s. 384-395.

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Michael, H. ; Härkönen, Pirkko ; Kangas, L. ; Vaananen, H. K. ; Hentunen, T. A. / Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro. I: British Journal of Pharmacology. 2007 ; Vol. 151, Nr. 3. s. 384-395.

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TY - JOUR

T1 - Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro

AU - Michael, H.

AU - Härkönen, Pirkko

AU - Kangas, L.

AU - Vaananen, H. K.

AU - Hentunen, T. A.

N1 - Department affilation moved from v1000588 (Tumour Biology, Malmö) to v1000562 (Department of Translational Medicine) on 2016-01-18 14:39:32.

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - bone

KW - osteoclast differentiation

KW - raloxifene

KW - tamoxifen

KW - ospemifene

KW - osteoprotegerin

KW - resorption

U2 - 10.1038/sj.bjp.0707232

DO - 10.1038/sj.bjp.0707232

M3 - Article

VL - 151

SP - 384

EP - 395

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 1476-5381

IS - 3

ER -