Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone-derived cells.
Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone-derived cells.
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DOI：
10.1074/jbc.m110.198713
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发表时间：
2011-04-01
期刊：
影响因子：
--
通讯作者：
Mobasheri A
中科院分区：
文献类型：
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作者：
Shakibaei M;Buhrmann C;Mobasheri A
白藜芦醇是一种多酚类植物雌激素，已被证明具有有效的抗氧化，抗炎和抗分解代谢的特性。骨吸收增加和成骨细胞活性降低导致骨吸收和骨量丢失。这些变化与类风湿性关节炎和骨质疏松症的病理过程有关。NF-κB配体受体激活剂（RANKL）是TNF超家族的成员，是骨丢失的主要介质。在这项研究中，我们研究了白藜芦醇对体外高密度骨培养中骨形态发生过程中RANKL的影响。未经处理的骨源性细胞培养物产生组织良好的骨样结构，具有骨特异性基质。RANKL处理诱导形成抗酒石酸酸性磷酸酶阳性多核细胞，表现出破骨细胞的形态学特征。RANKL可诱导NF-κB活化，而白藜芦醇预处理可完全抑制NF-κ B的活化，并抑制IκBα激酶的活化和IκBα的磷酸化和降解。RANKL上调p300（一种组蛋白乙酰转移酶）表达，进而促进NF-κB的乙酰化。白藜芦醇可抑制RANKL诱导的NF-κB乙酰化和核转位，并呈时间和浓度依赖性。此外，白藜芦醇激活Sirt-1（一种组蛋白脱乙酰酶）可诱导骨源性和前成骨细胞中Sirt-1-p300的结合，导致RANKL诱导的NF-κB脱乙酰化，抑制NF-κB转录激活和破骨细胞生成。与白藜芦醇共处理激活骨转录因子Cbfa-1和Sirt-1，并诱导Sirt-1-Cbfa-1复合物的形成。总体而言，这些结果表明，白藜芦醇活化的Sirt-1在调节体外骨形成中的成骨细胞活性与成骨细胞活性之间的平衡中起着关键作用，从而突出了其治疗骨质疏松症和类风湿性关节炎相关骨丢失的治疗潜力。
Resveratrol is a polyphenolic phytoestrogen that has been shown to exhibit potent anti-oxidant, anti-inflammatory, and anti-catabolic properties. Increased osteoclastic and decreased osteoblastic activities result in bone resorption and loss of bone mass. These changes have been implicated in pathological processes in rheumatoid arthritis and osteoporosis. Receptor activator of NF-κB ligand (RANKL), a member of the TNF superfamily, is a major mediator of bone loss. In this study, we investigated the effects of resveratrol on RANKL during bone morphogenesis in high density bone cultures in vitro. Untreated bone-derived cell cultures produced well organized bone-like structures with a bone-specific matrix. Treatment with RANKL induced formation of tartrate-resistant acid phosphatase-positive multinucleated cells that exhibited morphological features of osteoclasts. RANKL induced NF-κB activation, whereas pretreatment with resveratrol completely inhibited this activation and suppressed the activation of IκBα kinase and IκBα phosphorylation and degradation. RANKL up-regulated p300 (a histone acetyltransferase) expression, which, in turn, promoted acetylation of NF-κB. Resveratrol inhibited RANKL-induced acetylation and nuclear translocation of NF-κB in a time- and concentration-dependent manner. In addition, activation of Sirt-1 (a histone deacetylase) by resveratrol induced Sirt-1-p300 association in bone-derived and preosteoblastic cells, leading to deacetylation of RANKL-induced NF-κB, inhibition of NF-κB transcriptional activation, and osteoclastogenesis. Co-treatment with resveratrol activated the bone transcription factors Cbfa-1 and Sirt-1 and induced the formation of Sirt-1-Cbfa-1 complexes. Overall, these results demonstrate that resveratrol-activated Sirt-1 plays pivotal roles in regulating the balance between the osteoclastic versus osteoblastic activity result in bone formation in vitro thereby highlighting its therapeutic potential for treating osteoporosis and rheumatoid arthritis-related bone loss.