Trolox Prevents Osteoclastogenesis by Suppressing RANKL Expression and Signaling
Trolox Prevents Osteoclastogenesis by Suppressing RANKL Expression and Signaling
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DOI：
10.1074/jbc.m806941200
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发表时间：
2009-05-15
影响因子：
4.8
通讯作者：
Lee, Zang Hee
中科院分区：
文献类型：
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作者：
Lee, Jong-Ho;Kim, Ha-Neui;Lee, Zang Hee
过量的NF-κ B配体（RANKL）信号传导的受体激活剂导致破骨细胞形成和骨吸收增强。因此，下调RANKL表达或其下游信号可能是治疗病理性骨丢失的治疗方法。在这项研究中，我们研究了水溶性维生素E类似物Trolox对破骨细胞生成和RANKL信号传导的影响。Trolox通过消除成骨细胞中的RANKL诱导，有效抑制骨髓细胞-成骨细胞共培养中白细胞介素-1诱导的破骨细胞形成。这种RANKL降低归因于通过下调环氧合酶-2活性减少前列腺素E-2的产生。我们还发现Trolox以可逆方式抑制巨噬细胞集落刺激因子加RANKL诱导的骨髓巨噬细胞破骨细胞形成。Trolox仅在培养的早期阶段有效，这意味着它靶向早期破骨细胞前体。Trolox预处理不影响RANKL诱导的早期信号通路，包括MAPK、NF-κ B和Akt。我们发现Trolox通过抑制c-Fos蛋白的翻译来下调RANKL对c-Fos蛋白的诱导。c-Fos的异位过表达挽救了骨髓巨噬细胞中Trolox对破骨细胞生成的抑制。Trolox还抑制白细胞介素-1诱导的小鼠颅骨破骨细胞形成和骨丢失。总之，我们的研究结果表明，Trolox通过抑制成骨细胞中RANKL诱导和破骨细胞前体中c-Fos表达来防止破骨细胞形成和骨丢失。
Excessive receptor activator of NF-kappa B ligand (RANKL) signaling causes enhanced osteoclast formation and bone resorption. Thus, down-regulation of RANKL expression or its downstream signals may be a therapeutic approach to the treatment of pathological bone loss. In this study, we investigated the effects of Trolox, a water-soluble vitamin E analogue, on osteoclastogenesis and RANKL signaling. Trolox potently inhibited interleukin-1-induced osteoclast formation in bone marrow cell-osteoblast coculture by abrogating RANKL induction in osteoblasts. This RANKL reduction was attributed to the reduced production of prostaglandin E-2 via a down-regulation of cyclooxygenase-2 activity. We also found that Trolox inhibited osteoclast formation from bone marrow macrophages induced by macrophage colony-stimulating factor plus RANKL in a reversible manner. Trolox was effective only when present during the early stage of culture, which implies that it targets early osteoclast precursors. Pretreatment with Trolox did not affect RANKL-induced early signaling pathways, including MAPKs, NF-kappa B, and Akt. We found that Trolox down-regulated the induction by RANKL of c-Fos protein by suppressing its translation. Ectopic overexpression of c-Fos rescued the inhibition of osteoclastogenesis by Trolox in bone marrow macrophages. Trolox also suppressed interleukin-1-induced osteoclast formation and bone loss in mouse calvarial bone. Taken together, our findings indicate that Trolox prevents osteoclast formation and bone loss by inhibiting both RANKL induction in osteoblasts and c-Fos expression in osteoclast precursors.