Kawatani Makoto, Okumura Hideo, Honda Kaori, Kanoh Naoki, Muroi Makoto, Dohmae Naoshi, Takami Masamichi, Kitagawa Mitsuhiro, Futamura Yushi, Imoto Masaya, Osada Hiroyuki
Antibiotics Laboratory, Chemical Biology Department, and Biomolecular Characterization Team, Advanced Technology Support Division, Advanced Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11691-6. doi: 10.1073/pnas.0712239105. Epub 2008 Aug 11.
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 I (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.
破骨细胞是源自造血干细胞的具有骨吸收功能的多核细胞，与许多骨相关疾病有关，如骨质疏松症。靶向破骨细胞的小分子抑制剂是研究破骨细胞生物学和开发抗吸收药物的宝贵工具。在此，我们发现天然产物格费林的甲酯甲基格费林（M-GFN）可抑制破骨细胞生成。通过使用固定有M-GFN的珠子，乙二醛酶I（GLO1）被鉴定为一种M-GFN结合蛋白。在破骨细胞祖细胞中敲低GLO1并用已有的GLO1抑制剂处理会干扰破骨细胞的生成，这表明破骨细胞生成需要GLO1活性。在细胞中，GLO1在甲基乙二醛等2-氧代醛的解毒过程中起关键作用。M-GFN在体外和原位均抑制GLO1的酶活性。此外，GLO1/M-GFN复合物的共晶体结构揭示了M-GFN在GLO1活性位点的结合模式。这些结果表明M-GFN靶向GLO1，从而抑制破骨细胞生成。
