Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression
Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression
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DOI：
10.1073/pnas.130200197
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发表时间：
2000-07-05
影响因子：
11.1
通讯作者：
Pike, JW
中科院分区：
文献类型：
--
作者：
Shevde, NK;Bendixen, AC;Pike, JW
绝经后卵巢功能丧失导致骨转换显著增加，骨形成和骨吸收严重失衡。这种不平衡导致骨小梁质量的进行性损失，最终导致骨质疏松症，部分原因是破骨细胞生成增加。功能性破骨细胞的形成增强似乎是破骨细胞生成细胞因子（如IL-1、肿瘤坏死因子和IL-6）的支持细胞增加的结果，所有这些细胞因子均受雌激素负调控。我们发现雌激素可以通过一种不需要基质细胞介导的雌激素受体依赖性机制抑制核因子-κ B配体受体激活因子（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为多核抗酒石酸酸性磷酸酶阳性破骨细胞。这种抑制具有剂量依赖性、异构体特异性，并可被ICI 182780逆转。此外，骨保护类似物他莫昔芬和雷洛昔芬模拟雌激素的作用。雌激素阻断RANKL/M-CSF诱导的激活蛋白-1依赖性转录，可能通过直接调节c-Jun活性。这种效应是雌激素受体调节c-Jun表达及其通过c-Jun N-末端激酶磷酸化的经典核活性的结果。我们的研究结果表明，雌激素调节破骨细胞的形成，通过下调破骨细胞生成细胞因子的表达从支持细胞和直接抑制RANKL诱导的破骨细胞分化。
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-kappa B 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.