Passeri G, Girasole G, Jilka R L, Manolagas S C
Section of Endocrinology and Metabolism, Veterans Administration Medical Center, Indianapolis, Indiana 46202.
Endocrinology. 1993 Aug;133(2):822-8. doi: 10.1210/endo.133.2.8393776.
We have previously shown that cytokine-induced production of interleukin-6 (IL-6) by cultured bone marrow-derived stromal and osteoblastic cells is inhibited by 17 beta-estradiol, and that estrogen withdrawal (ovariectomy) in mice causes an up-regulation of osteoclast development which can be prevented by a neutralizing antibody against IL-6 or estrogen replacement. To directly establish the link between estrogen loss and altered IL-6 production, implied by our earlier studies, we have now compared IL-6 production in ex vivo cultures of bone marrow cells from mice that were sham operated, ovariectomized, or ovariectomized and treated with 17 beta-estradiol. In addition, we have examined the effect of the in vitro withdrawal of estrogens from primary cell cultures of neonatal murine calvaria on IL-6 production. IL-6 production in ex vivo cultures of bone marrow cells maintained in the presence of 1,25-dihydroxyvitamin D3 or PTH was greater in marrow cells from ovariectomized mice than in those from sham-operated animals or ovariectomized animals receiving estrogen replacement. In line with this finding, addition of 17 beta-estradiol to calvaria cell cultures followed by withdrawal of the steroid caused an increase in the amount of IL-6 produced in response to the subsequent stimulation of these cultures with IL-1 or PTH compared to that in cultures that had never been treated with estradiol; when the inactive isomer 17 alpha-estradiol was used, no change in IL-6 production was observed. These results establish that estrogen loss causes an up-regulation of IL-6 production by bone marrow cells and that a similar phenomenon can be elicited in vitro by withdrawal of 17 beta-estradiol from primary cultures of bone cells.
我们之前已经表明，培养的骨髓来源的基质细胞和成骨细胞经细胞因子诱导产生白细胞介素-6（IL-6）的过程受到17β-雌二醇的抑制，并且小鼠体内雌激素撤退（卵巢切除术）会导致破骨细胞发育上调，而这种上调可通过抗IL-6中和抗体或雌激素替代来预防。为了直接建立我们早期研究所暗示的雌激素丧失与IL-6产生改变之间的联系，我们现在比较了假手术、卵巢切除或卵巢切除并用17β-雌二醇治疗的小鼠骨髓细胞体外培养物中IL-6的产生情况。此外，我们还研究了从小鼠新生颅骨原代细胞培养物中体外撤除雌激素对IL-6产生的影响。在1,25-二羟基维生素D3或甲状旁腺激素存在的情况下，卵巢切除小鼠的骨髓细胞体外培养物中IL-6的产生量高于假手术动物或接受雌激素替代的卵巢切除动物的骨髓细胞。与此发现一致，在颅骨细胞培养物中添加17β-雌二醇后再撤除该类固醇，与从未用雌二醇处理过的培养物相比，随后用IL-1或甲状旁腺激素刺激这些培养物时，IL-6的产生量会增加；当使用无活性异构体17α-雌二醇时，未观察到IL-6产生的变化。这些结果表明，雌激素丧失会导致骨髓细胞IL-6产生上调，并且从骨细胞原代培养物中撤除17β-雌二醇在体外也能引发类似现象。
