Michael H, Härkönen P L, Kangas L, Väänänen H K, Hentunen T A
Department of Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland.
Br J Pharmacol. 2007 Jun;151(3):384-95. doi: 10.1038/sj.bjp.0707232. Epub 2007 Apr 10.
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.
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.
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.
Tamoxifen had an oestrogen receptor dependent, direct, inhibitory effect 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.
已研发出几种在骨细胞中具有雌激素激动作用且不会增加乳腺癌和子宫内膜癌风险的选择性雌激素受体调节剂（SERM）。在此，我们研究了不同类型的SERM对体外破骨细胞分化、骨吸收和凋亡的影响。
将人外周血来源的CD14 + 单核细胞在含有RANKL、M - CSF、TNF - α和地塞米松的条件下于牛骨切片上培养7天。此外，在甲状旁腺激素存在的情况下，将CD14 + 单核细胞与人SaOS - 2或MG - 63骨肉瘤细胞共培养。破骨细胞培养物用不同的SERM处理。TRACP + 多核细胞和I型胶原C末端肽分别用作破骨细胞形成和骨吸收的标志物。
在CD14 + 单核细胞培养物中，他莫昔芬直接抑制人破骨细胞形成和骨吸收，而雷洛昔芬和奥昔芬没有抑制作用。在与SaOS - 2或MG - 63细胞的共培养物中，奥昔芬、雷洛昔芬以及他莫昔芬均以浓度依赖性方式抑制破骨细胞形成。这种抑制作用与骨保护素产生增加有关。抗雌激素ICI 182 780完全逆转了这些SERM的作用。
他莫昔芬对人破骨细胞分化和骨吸收具有雌激素受体依赖性的直接抑制作用，而奥昔芬和雷洛昔芬需要成骨细胞才能实现类似的抑制作用。奥昔芬和雷洛昔芬的作用是通过雌激素受体介导的，其机制涉及在与成骨细胞来源的骨肉瘤细胞共培养时旁分泌诱导骨保护素。
