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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression
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Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression

机译：雌激素通过涉及c-Jun抑制的基质细胞独立机制抑制RANK配体诱导的破骨细胞分化

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Loss of ovarian function following menopause results in a substantial increase in bone turnover and a critical imbalance between bone formation and resorption. This imbalance leads to a progressive loss of trabecular bone mass and eventually osteoporosis, in part the result of increased osteoclastogenesis. Enhanced formation of functional osteoclasts appears to be the result of increased elaboration by support cells of osteoclastogenic cytokines such as IL-1, tumor necrosis factor, and IL-6, all of which are negatively regulated by estrogens. We show here that estrogen can suppress receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF)-induced differentiation of myelomonocytic precursors into multinucleated tartrate-resistant acid phosphatase-positive osteoclasts through an estrogen receptor-dependent mechanism that does not require mediation by stromal cells. This suppression is dose-dependent, isomer-specific, and reversed by ICI 182780. Furthermore, the bone-sparing analogues tamoxifen and raloxifene mimic estrogen's effects. Estrogen blocks RANKL/M-CSF-induced activator protein-1-dependent transcription, likely through direct regulation of c-Jun activity. This effect is the result of a classical nuclear activity by estrogen receptor to regulate both c-Jun expression and its phosphorylation by c-Jun N-terminal kinase. Our results suggest that estrogen modulates osteoclast formation both by down-regulating the expression of osteoclastogenic cytokines from supportive cells and by directly suppressing RANKL-induced osteoclast differentiation.
机译：绝经后卵巢功能丧失导致骨转换率显着增加以及骨形成和吸收之间的严重失衡。这种失衡导致小梁骨质量逐渐丧失，最终导致骨质疏松，部分原因是破骨细胞增多。功能性破骨细胞形成的增强似乎是破骨细胞生成细胞因子（例如IL-1，肿瘤坏死因子和IL-6）的支持细胞对精细细胞形成的增强作用的结果，这些因子均受雌激素负调节。我们在这里显示雌激素可以抑制雌激素受体依赖性的NF-κB配体（RANKL）和巨噬细胞集落刺激因子（M-CSF）诱导的骨髓单核细胞前体分化成多核抗酒石酸酸性磷酸酶阳性破骨细胞的受体激活剂不需要基质细胞介导的机制。这种抑制作用是剂量依赖性的，异构体特异性的，并被ICI 182780逆转。此外，保骨类似物他莫昔芬和雷洛昔芬模拟雌激素的作用。雌激素可能通过直接调节c-Jun活性来阻断RANKL / M-CSF诱导的激活蛋白1依赖性转录。这种作用是雌激素受体经典核活性调节c-Jun表达及其c-Jun N端激酶磷酸化的结果。我们的结果表明，雌激素通过下调来自支持细胞的破骨细胞因子的表达以及直接抑制RANKL诱导的破骨细胞分化来调节破骨细胞的形成。

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