Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association.
Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association.
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DOI：
10.1016/j.bone.2015.02.007
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发表时间：
2015-06
期刊：
影响因子：
4.1
通讯作者：
Frenkel, Baruch
中科院分区：
文献类型：
--
作者：
Martin, Anthony;Xiong, Jian;Koromila, Theodora;Ji, Jie S.;Chang, Stephanie;Song, Yae S.;Miller, Jonathan L.;Han, Chun-Ya;Kostenuik, Paul;Krum, Susan A.;Chimge, Nyam-Osor;Gabet, Yankel;Frenkel, Baruch
除了深入研究成骨细胞转录因子RUNX2在骨形成中的作用外，它还促进破骨细胞的形成和骨吸收。在此，我们证明了17-雌二醇(17β-estadiol，E_2)在体内可抑制骨转换，在体外可抑制RUNX2的活性，在共培养条件下可强烈抑制RUNX2介导的成骨细胞驱动的破骨细胞生成。为了解释其潜在的机制，我们在原代小鼠前成骨细胞中诱导了RUNX2的过早表达，这导致了共培养的脾细胞向成熟的破骨细胞分化。这归因于RUNX2介导的RANKL分泌的增加(通过ELISA法)，以及RUNX2介导的RANKL与成骨细胞膜结合的增加(通过共聚焦荧光显微镜观察)。瞬时表达的GFP-RANKL重现了与成骨细胞膜的结合增加。E2阻断RUNX2介导的膜相关RANKL和GFP-RANKL的增加，以及伴随的破骨细胞生成。Runx2介导的RANKL细胞重分布部分归因于OPG表达的减少，但无论是否存在RUNX2，E2都不影响OPG的表达。无论破骨前细胞是来自野生型还是雌激素受体α(ERα)基因敲除的小鼠，E2都能减少RUNX2介导的破骨细胞生成，这表明激活的ERα通过作用于成骨细胞而抑制成骨细胞驱动的破骨细胞生成，可能针对RUNX2。此外，在共培养实验中，选择性ER调节剂(SERM)他莫昔芬和雷洛昔芬模拟E2，取消成骨细胞RUNX2对破骨细胞分化的刺激作用。因此，E2拮抗RUNX2介导的RANKL转运和随后的破骨细胞形成。靶向RUNX2和/或调节RANKL转运的下游机制可能会导致改进的SERM的开发，并可能导致高周转率骨病的非激素治疗方法的发展。
In addition to its thoroughly investigated role in bone formation, the osteoblast master transcription factor RUNX2 also promotes osteoclastogenesis and bone resorption. Here we demonstrate that 17β-estradiol (E2), which is known to attenuate bone turnover in vivo and RUNX2 activity in vitro, strongly inhibits RUNX2-mediated osteoblast-driven osteoclastogenesis in co-cultures. Towards deciphering the underlying mechanism, we induced premature expression of RUNX2 in primary murine pre-osteoblasts, which resulted in robust differentiation of co-cultured splenocytes into mature osteoclasts. This was attributable to RUNX2-mediated increase in RANKL secretion, determined by ELISA, as well as to RUNX2-mediated increase in RANKL association with the osteoblast membrane, demonstrated using confocal fluorescence microscopy. The increased association with the osteoblast membrane was recapitulated by transiently expressed GFP-RANKL. E2 abolished the RUNX2-mediated increase in membrane-associated RANKL and GFP-RANKL, as well as the concomitant osteoclastogenesis. RUNX2-mediated RANKL cellular redistribution was attributable in part to a decrease in Opg expression, but E2 did not influence Opg expression either in the presence or absence of RUNX2. Diminution of RUNX2-mediated osteoclastogenesis by E2 occurred regardless of whether the pre-osteoclasts were derived from wild type or estrogen receptor alpha (ERα)-knockout mice, suggesting that activated ERα inhibited osteoblast-driven osteoclastogenesis by acting in osteoblasts, possibly targeting RUNX2. Furthermore, the selective ER modulators (SERMs) tamoxifen and raloxifene mimicked E2 in abrogating the stimulatory effect of osteoblastic RUNX2 on osteoclast differentiation in the co-culture assay. Thus, E2 antagonizes RUNX2-mediated RANKL trafficking and subsequent osteoclastogenesis. Targeting RUNX2 and/or downstream mechanisms that regulate RANKL trafficking may lead to the development of improved SERMs and possibly non-hormonal therapeutic approaches to high turnover bone disease.
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影响因子：
15.9
作者：
Eghbali-Fatourechi, G;Khosla, S;Riggs, BL
通讯作者：
Riggs, BL
影响因子：
4.1
作者：
Kalajzic, Ivo;Matthews, Brya G.;Torreggiani, Elena;Harris, Marie A.;Pajevic, Paola Divieti;Harris, Stephen E.
通讯作者：
Harris, Stephen E.
影响因子：
5.3
作者：
Geoffroy, V;Kneissel, M;Matthias, P
通讯作者：
Matthias, P
影响因子：
6.2
作者：
CVETKOVIC, M;MANN, GN;EPSTEIN, S
通讯作者：
EPSTEIN, S
影响因子：
37.3
作者：
Baniwal SK;Khalid O;Gabet Y;Shah RR;Purcell DJ;Mav D;Kohn-Gabet AE;Shi Y;Coetzee GA;Frenkel B
通讯作者：
Frenkel B