Morimoto Riyo, Uehara Shunsuke, Yatsushiro Shouki, Juge Narinobu, Hua Zhaolin, Senoh Shigenori, Echigo Noriko, Hayashi Mitsuko, Mizoguchi Toshihide, Ninomiya Tadashi, Udagawa Nobuyuki, Omote Hiroshi, Yamamoto Akitsugu, Edwards Robert H, Moriyama Yoshinori
Laboratory of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
EMBO J. 2006 Sep 20;25(18):4175-86. doi: 10.1038/sj.emboj.7601317. Epub 2006 Sep 7.
Osteoclasts are involved in the catabolism of the bone matrix and eliminate the resulting degradation products through transcytosis, but the molecular mechanism and regulation of transcytosis remain poorly understood. Upon differentiation, osteoclasts express vesicular glutamate transporter 1 (VGLUT1), which is essential for vesicular storage and subsequent exocytosis of glutamate in neurons. VGLUT1 is localized in transcytotic vesicles and accumulates L-glutamate. Osteoclasts secrete L-glutamate and the bone degradation products upon stimulation with KCl or ATP in a Ca2+-dependent manner. KCl- and ATP-dependent secretion of L-glutamate was absent in osteoclasts prepared from VGLUT1-/- knockout mice. Osteoclasts express mGluR8, a class III metabotropic glutamate receptor. Its stimulation by a specific agonist inhibits secretion of L-glutamate and bone degradation products, whereas its suppression by a specific antagonist stimulates bone resorption. Finally, it was found that VGLUT1-/- mice develop osteoporosis. Thus, in bone-resorbing osteoclasts, L-glutamate and bone degradation products are secreted through transcytosis and the released L-glutamate is involved in autoregulation of transcytosis. Glutamate signaling may play an important role in the bone homeostasis.
破骨细胞参与骨基质的分解代谢，并通过转胞吞作用清除产生的降解产物，但转胞吞作用的分子机制和调控仍知之甚少。在分化过程中，破骨细胞表达囊泡型谷氨酸转运体1（VGLUT1），这对于神经元中谷氨酸的囊泡储存和随后的胞吐作用至关重要。VGLUT1定位于转胞吞囊泡中并积累L-谷氨酸。破骨细胞在受到KCl或ATP刺激时以Ca2+依赖的方式分泌L-谷氨酸和骨降解产物。在从VGLUT1-/-基因敲除小鼠制备的破骨细胞中，不存在KCl和ATP依赖的L-谷氨酸分泌。破骨细胞表达III类代谢型谷氨酸受体mGluR8。其特异性激动剂对它的刺激会抑制L-谷氨酸和骨降解产物的分泌，而其特异性拮抗剂对它的抑制则会刺激骨吸收。最后，发现VGLUT1-/-小鼠会发生骨质疏松症。因此，在进行骨吸收的破骨细胞中，L-谷氨酸和骨降解产物通过转胞吞作用分泌，释放的L-谷氨酸参与转胞吞作用的自动调节。谷氨酸信号传导可能在骨稳态中起重要作用。
