The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I
The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I
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DOI：
10.1073/pnas.0712239105
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发表时间：
2008-08-19
影响因子：
11.1
通讯作者：
Osada, Hiroyuki
中科院分区：
文献类型：
--
作者：
Kawatani, Makoto;Okumura, Hideo;Osada, Hiroyuki
破骨细胞是一种来源于造血干细胞的多核骨吸收细胞，与骨质疏松症等多种骨相关疾病有关。破骨细胞靶向小分子抑制剂是研究破骨细胞生物学和开发抗骨吸收药物的重要工具。在这里，我们发现甲基-吉非林（M-GFN），天然产物吉非林的甲酯，抑制破骨细胞生成。通过使用M-GFN-固定化珠，鉴定了谷胱甘肽酶1（GLO 1）为M-GFN-结合蛋白。GLO 1敲低和治疗与一个既定的GLO 1抑制剂在破骨细胞祖细胞干扰破骨细胞的产生，这表明GLO 1活性是破骨细胞生成所需的。在细胞中，GLO 1在2-氧代醛（如甲基乙二醛）的解毒中起关键作用。M-GFN在体外和原位均能抑制GLO 1的酶活性。此外，GLO 1/M-GFN复合物的共晶结构揭示了M-GFN在GLO 1活性位点的结合模式。这些结果表明，M-GFN靶向GLO 1，导致破骨细胞生成的抑制。
Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFN-immobilized beads, glyoxalase 1 (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.